\r\n\tThe present book intends to provide to the reader a comprehensive overview of the state of art in empathy studies, embracing the different theoretical points of view and illustrating the advanced research such as the application of new technologies to promote perspective-taking. The critical aspects and the future directions of the study on empathy will also be presented.
",isbn:"978-1-80356-612-2",printIsbn:"978-1-80356-611-5",pdfIsbn:"978-1-80356-613-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"4c1042dfe15aa9cea6019524c4cbff38",bookSignature:"Ph.D. Sara Ventura",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11443.jpg",keywords:"Theoretical Model, Skill, Perspective Taking, Training Programs, Practical Implications, Advanced Research, Future Directions, Virtual Reality, Augmented Reality, New Trends, Assistive Technology",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 1st 2022",dateEndSecondStepPublish:"June 8th 2022",dateEndThirdStepPublish:"August 7th 2022",dateEndFourthStepPublish:"October 26th 2022",dateEndFifthStepPublish:"December 25th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Passionate researcher in the application of new technologies to psychological treatments, neuro-rehabilitation, human behavior, and the evolution of the human-computer interaction. In 2017 Dr. Ventura won a competitive grant (Santiago Grisolia) at the University of Valencia at LABPSITEC group, where she was awarded her Ph.D. degree, supervised by Prof. Rosa Baños at the University of Valencia, and co-directed by Prof. Giuseppe Riva of the Catholic University of Milan.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura",profilePictureURL:"https://mts.intechopen.com/storage/users/227763/images/system/227763.jpg",biography:"Sara Ventura gained a B.Sc in Psychology at the University of Padua (Italy) in 2013 and an M.Sc. in Ergonomic Psychology at the Catholic University of Milan (Italy) in 2015. In 2016, she carried out a postgraduate training at Universidad Nacional Autónoma de Mexico (Mexico) at the Ciberpsychology lab, working on a rehabilitation protocol for people with acquired brain injury through Virtual Reality. In 2020, Sara gained the Ph.D. in Clinical Psychology at University of Valencia (Spain) working with the LabPsitec group and focusing her research on the study of embodiment and empathy with the support of Virtual Reality. Actually, she is working both with Alma Mater Studiorum – University of Bologna (Italy), and the University of Valencia (Spain) on the fields of embodiment, stroke rehabilitation, empathy and patient care. Her research interests mainly focus on the adoption of new technologies, particularly Virtual/Augmented Reality and Artificial Intelligence for the psycho-social wellbeing with clinical and non-clinical populations, the study of human-computer interaction, and the user experience. She is the author of several scientific papers and various presentations at national and international conferences.",institutionString:"University of Valencia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Valencia",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"455410",firstName:"Dajana",lastName:"Jusic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/455410/images/20500_n.jpeg",email:"dajana.j@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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1. Introduction
Presently, researchers are paying considerable attention to devise eco-friendly approaches for organic transformations. There has been a significant hike in interest among the scientists for more environmentally acceptable processes in the chemical industries. Synthetic chemistry has led us to the development of more potent structural analogs of natural products. The high therapeutic efficiency, bioavailability, and pharmacological characteristics of synthetic molecules have increased their use in medicinal chemistry as compared to natural products. Pharmaceutical chemistry encompasses the design, synthesis, and evaluation of compounds. In designing drugs, there is an upsurge demand for eco-benign pathways to accomplish the green aspects of chemistry. Novel green pathways play a vital role in the synthetic chemistry field by eradication of harmful solvents and chemicals or suitable handling of waste materials. The quest for new and proficient approaches for the synthesis of numerous biologically active scaffolds has made click chemistry a promising approach in chemistry. Click chemistry is a fruitful approach for the fabrication of molecules.
Huisgen and co-workers demonstrated a click reaction, Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC). The advanced use of this reaction and click chemistry was introduced by K. Barry Sharpless in 2001. The term click chemistry not only refers to the reaction which occurs fast but also to those that involve twelve principles of green chemistry i.e. selective, easier product isolation, mild reaction condition, high yield, good atom economy, avoid toxic catalyst and solvent, and so on. They encompass reactions that are high yielding, fast, modular, and wide in scope. They are practical and tolerant for a variety of functional groups. Finally, the product isolation is expected to be effortless due to lack of by-products. These vast characteristics make click chemistry a powerful tool that paves a path in several fields of research viz. designing of drugs and lead structures [1, 2, 3, 4]. Therefore the synergy between these disciplines has given rise to an area of intense research activity. The click chemistry has been such an engrossing topic of research that a lot of review articles have been published so far which explained its applicability in various fields of chemistry like manufacturing and alteration of metal–organic frameworks [5], making devices in bio-sensing system for responsive copper identification [6], designing bio-adhesives for hastening wound closure [7], in virus-related research [8], generation of biosensors [9], proteomics analysis [10], in strategy for indirect 18F-labeling [11], in vivo bio-imaging [12], to identify the interaction of curcumin with protein [13], synthesis of polymers and material science [14], for surface modification [15], and so on. In this chapter, the state-of-art modernization with a particular focus on click chemistry assisted synthesis and their uses in various fields of science have been discussed. An attempt has been done to prepare an outline of the importance of click chemistry and its foremost requirement in the research area. It is predicted that this methodical study will pave the way for future opportunities in this direction and design of safer, economical, and eco-friendly pathways.
2. Green aspects of click reactions
According to Sir John Cornforth, a Noble Prize laureate in chemistry in 1975, ideal reaction has been defined as “The ideal chemical process is that which a one-armed operator can perform by pouring the reactants into a bath-tub and collecting the pure product from the drain hole” [16]. Click reactions are designed in such a way that it involves all the twelve principles of green chemistry. Click chemistry includes synthetic methods that are designed to maximize the inclusion of all resources used in the process into the final product. Due to involvement of addition and rearrangement reactions, they have high atom economy. The products are designed with maximum efficacy and minimum cytotoxicity [17]. The green aspects have been depicted in Figure 1.
Figure 1.
Green aspects of click chemistry.
3. Role of click reactions in synthetic chemistry
Click chemistry includes a cluster of powerful linking chemical reactions that are easy to perform, have high yields, require no or minimal purification, and are flexible in the unification of different structures without the prerequisite of protection steps. Molecular diversity, modularity, and efficiency are essential in synthetic organic chemistry and expected to be involved in the preparation of several complexes and multi-purpose compounds. In general “Click Chemistry” is a class of biocompatible reactions, to link desired substrates with particular biomolecules. Natural products are produced by joining tiny modular units via biosynthesis as well as photosynthesis [18]. Click chemistry provides a route for the synthesis of several heterocyclic scaffolds, amino acids, triazole-fused heterocycles, peptides, and chromophores [19, 20].
3.1 Classification of click reaction
There is no specific classification of click reactions. The chief requisite for “Click Chemistry” is well met by reactions that take place in nature and their mimic in the laboratory is the closest and most desirable to the mind and spirit of most synthetic organic chemists. Usually, four main classifications of click reactions have been identified [21, 22].
Cycloadditions: These refers to 1,3-dipolar cycloadditions reactions and hetero-Diels-Alder cycloadditions.
Nucleophilic ring-opening reactions: This classification belongs to the opening of strained heterocyclic electrophiles, such as epoxides, aziridines, aziridinium ions, cyclic sulfates episulfonium ions, etc.
Nucleophilic addition reaction: It includes the reaction of carbonyl groups like formation of hydrazones, urease, thiourease, oxime ethers, aromatic heterocycles, amides, etc.
Additions to carbon–carbon multiple bonds: It involves epoxidation, dihydroxylation, aziridination, nitrosyl halide addition, sulfenyl halide addition, and certain Michael additions.
Presently, click chemistry inspired synthesis has become the most fascinating approach. Several multi-component reactions have been designed in an eco-friendly manner like aldol condensation followed by Michael addition, Ugi reaction/aldol reaction, Ugi reaction/Huisgen reaction, Ugi Reaction/Diels-Alder reaction, Ugi reaction/Heck reactions, Michael addition/Mannich reaction, etc. [23]
The most famous click reaction is the classical reaction between an azide and an alkyne. Both the substrates do not react under physiological conditions and go through a cycloaddition reaction only at a particular temperature. The uncatalyzed reaction is usually slow and not regio-selective. On the other hand, it was found that the use of electron-deficient terminal alkynes can cause 1,4-regioselectivity to a great extent. These factors limit the use of uncatalyzed Huisgen cycloaddition as an efficient conjugation pathway [24].
3.2 Metal-catalyzed approach for the click synthesis
3.2.1 Synthesis of triazole derivatives
Metals have been used to catalyze several click reactions. The mechanism of metal catalyzed azide alkyne click reaction involves formation of π-alkynyl complex with metal followed by complexation of azide by metal of the π-coordinated triple bond. After cyclization, metallacycle is formed followed by the reductive elimination to afford the relevant 1,2,3-triazole. Several metal like Cu, Ru, Ag, Au, etc. have been employed to accomplish click reactions [25, 26, 27, 28]. This section has been divided in two subsections:
3.2.1.1 Metal-catalyzed synthesis of triazole derivatives
Transition metals have been used to catalyze several organic reactions as they provide large surface area and they have vacant d-orbitals due to which they can show variable oxidation state that help in generation of intermediate for organic synthesis [29, 30]. The common process for the click reaction is the transition metal catalyzed synthesis of 1,2,3-triazoles. 1,3-dipolar cyclo-addition of an azide and an alkyne catalyzed by Cu is the most extensively used click-chemistry pathway due to its high selectivity and simplicity [31]. In 2014, Guo and co-workers synthesized β-cyclodextrin derivatives (1) using mono-6-azidocyclodextrin and aromatic aldehydes by CuI-catalyzed azide–alkyne cyclo-addition. The mono, di, and tri derivatives were synthesized upto 75% yield under mild reaction conditions [32] (Figure 2).
Figure 2.
Synthesis of β-cyclodextrin derivatives using click chemistry approach.
Later on, Kumar et al. [33] designed a library of new nucleosides (2 and 3) having 1,2,3-triazole scaffold at the 2″-position of the sugar nucleus. It was synthesized by 2″-azidouridine using the copper (I)-catalyzed Huisgen–Sharpless–Meldal 1,3-dipolar cyclo-addition reaction (Figure 3). The reaction gave 52–82% yield and 1,4-disubstituted 1,2,3-triazoles were obtained.
Figure 3.
Synthesis of library of traizole substituted nucleosides.
Tale and co-workers also synthesized 1,2,3-triazoles in excellent yields using (1-(4-methoxybenzyl)-1-H-1,2,3-triazol-4-yl)methanol (MBHTM) ligand (1.1 mol%) and CuSO4 (1 mol%) as a catalyst and sodium ascorbate (5 mol%) in DMSO:H2O(1:3) as a solvent [34]. Shamla and co-workers synthesized coumarin substituted triazole derivatives (4) in good yields using 4-bromomethylcoumarins, terminal alkynes, and sodium azide in the presence of triethylamine and CuI as a catalyst [35] (Figure 4).
Figure 4.
Synthesis of coumarin substituted triazole derivatives.
Yarlagadda et al. synthesized N-((l-benzyl-slH-l,2,3-triazol-5-yl) methyl)-4-(6-methoxy benzo[d]thiazol-2-yl)-2-nitrobenzamide derivatives (5) and examined their anti-microbial activity. Among these compounds, compounds 5a, 5 h, 5i possessed promising activity in comparison to standard drug ciprofloxacin and miconazole (Figure 5) [36].
Figure 5.
Synthesis of N-((l-benzyl-lH-l,2,3-triazol-5-yl) methyl)-4-(6-methoxy benzo[d]thiazol-2-yl)-2-nitrobenzamide derivatives.
Anand et al. designed Cu(I) catalyzed regio-selective synthesis of iso-indoline-1,3-dione linked 1,4 coumarinyl 1,2,3-triazoles (6) and Ru (II) catalyzed pathway of 1,5 coumarinyl 1,2,3-triazoles in high yields with no need for further purification (Figure 6) [37].
Figure 6.
Synthesis of iso-indoline-1,3-dione linked 1,4 coumarinyl 1,2,3-triazoles derivatives.
Anandhan et al. prepared a series of triazole-based macrocyclic amides (7) via click chemistry using CuSO4 (5 mol%), sodium ascorbate (10 mol %) in the presence of H2O/THF (1:1), RT. The synthesized compounds showed good anti-inflammatory activity although at low concentration (50 μg/mL) in comparison to the reference drug prednisolone (Figure 7) [38].
Figure 7.
Triazole based macrocyclic amides.
Li and co-workers designed triazole derivatives (8 and 9) by click chemistry using CuSO4∙5H2O (0.1 g) and ascorbic acid (0.1 g) in tBuOH/H2O as a solvent and investigated their applications to synthesize self-assembled membrane against copper corrosion. As per the investigation results, it was found that 2-(1-tosyl-1H-1,2,3-triazol-4-yl)-ethanol (TTE) (8) and 2-(1-tosyl-1H-1,2,3-triazol-4-yl)-propan-2-ol (TTP) (9) coating on film can sturdily decrease the corrosion caused by copper in 3 wt.% NaCl solution and the inhibition effectiveness of TTP and TTE were 93.1% and 89.4%, respectively (Figure 8) [39].
Figure 8.
Derivatives of triazole.
Savanur and co-workers developed facile click chemistry inspired synthesis of triazole ring fused coumarin and quinolinone derivatives using CuSO4 (10 mol%), sodium ascorbate (10 mol%), H2O:PEG, RT followed by K2CO3/DMF at 50–60 °C and examined their anti-microbial activity. Among the synthesized compounds, compounds 10j, 11 g and 12f displayed good anti-bacterial activities. Derivatives 10e and 10j were found highly active against yeast strains. Compound 11f was highly active against filamentous strain A. niger and yeast fungi [40] (Figure 9).
Figure 9.
Triazole ring fused coumarin and quinolinone derivatives.
Yarovaya et al. [41] fabricated a conjugate of cytisine with camphor having triazole ring using click chemistry pathway by employing CuSO4∙5H2O, sodium ascorbate, t-BuOH/H2O. The designed molecules were examined for in vitro antiviral activity against A/PuertoRico/8/34 influenza virus (H1N1). The compound (13) has highest inhibition activity with IC50 = 8 ± 1 μmol (Figure 10).
Figure 10.
Cytisine conjugated triazole derivative.
Khanapurmath et al. synthesized various derivatives of triazole by click chemistry approach using CuSO4 and ascorbic acid in H2O:DMF solvent and assessed them against Mycobacterium tuberculosis H37Rv. 6-Methyluracil and theophylline mono-triazole compounds 14(a-d) and bis-triazole compounds, 15(a-e) showed reasonable inhibition of M. tuberculosis H37Rv, with MIC values in the range of 55.62–115.62 μM. Benzimidazolone bis-triazole derivatives 16(a-n) inhibited M. tuberculosis H37Rv with MIC 2.35–18.34 μM (Figure 11) [42].
Figure 11.
Methyluracil and theophylline mono-triazole compounds and Bis-triazole compounds.
3.2.1.2 Metal Nano-particle based triazole synthesis
Green synthesis is the fundamental requirement of present synthetic protocol and use of nanoparticles (Nps) is one of the key tackle for organic transformations. NPs are microscopic particles with dimension between 1–100 nm. These are used as catalysts because they provide large surface area, high catalytic activity, nontoxic, heterogeneous nature, etc. In lieu of this, Chetia et al. designed copper Nps (nano particles) supported over hydrotalcite and used these Nps (15 mg) to catalyze 1,3 dipolar cycloaddition reaction to form 1,4 disubstituted-1,2,3-triazoles (17) (Figure 12) at room temperature using ethylene glycol as a solvent. The catalyst is heterogeneous, easily recyclable, and further reusable [43]. In this context, Poshala and co-workers developed copper Nps (0.1 mmol) using rongalite as a reducing agent and examined their catalytic efficiency in synthesizing triazole (18) derivatives in the presence of β-cyclodextrin (0.02 mmol) [44].
Figure 12.
Triazole derivatives.
Chavan et al. [45] designed a click chemistry assisted MCR strategy for the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles (19) using CuINps supported over cellulose (7 mol%) as a catalyst in the presence of DMF:Water (1:2) (Figure 13). The synthesized compounds were screened for anti-cancer activity against MCF-7, HeLa, MDA-MB-231, A-549, PANC-1 and THP-1. Compounds 19i and 19j were observed to be the most potent against MCF-7 with IC50 = 2.13 μM and 4.80 μM respectively. Compound 19 k was the most potent one against MDA-MB-231 with (IC50 = 3.78 μM). All the products were found to be safe against the human umbilical vein endothelial cells (HUVECs).
Elavarasan et al. prepared nano rod shaped triazine functional hierarchical mesoporous organic polymers (HMOP) containing Cu metal. This catalyst was used to synthesize triazole derivatives (20) via stirring at 80 °C in the presence of water as a solvent [46]. In the same year 2019, Gholampour et al. synthesized a library of 1,4-naphthoquinone-1,2,3-triazole hybrids (21) using CuSO4 (0.15 mmol) and sodium ascorbate (.05 mmol) catalyzed click chemistry approach from 2-(prop-2-ynylamino)naphthalene-1,4-dione and different azidomethyl-benzene analogs. The anti-cancer activity of synthesized compounds was anticipated against three cancer cell lines (MCF-7, HT-29 and MOLT-4) by MTT assay. The compound 21f possessed the highest activity [47]. In continuation to this, magnetic CuFe2O4/g-C3N4 hybrids were synthesized and their catalytic activity was examined in the synthesis of triazole derivatives (22 and 23) using terminal alkyne, azide, epoxide or haloarene (Figure 14) [48].
Figure 14.
Structures of different triazole derivatives.
Pourmohammad et al. synthesized (CuI@[PMMA-CO-MI]) (0.02 g) nano catalyst and employed them in the synthesis of triazole derivatives using terminal alkynes, α-haloketones or alkyl halides and sodium azide in H2O at RT to give 1,4-disubstitued 1,2,3-triazoles (24) (Figure 15). The catalyst being heterogenous and regioselective gave high yields in short reaction times [49].
Figure 15.
Triazole derivatives.
Thanh et al. [50] designed a hybrid structure of chromene and triazole by applying click chemistry approach for the synthesis of 1H-1,2,3-triazole-tethered 4H-chromene-D-glucose analogs (25) using Cu@MOF-5 (2 mol%) as a catalyst to afford 80–97.8% yields. The copper supported over metal organic frame work was found better catalyst in comparison to conventional catalysts viz. CuSO4.5H2O-sodium ascorbate, CuI, Cu Nps, CuIM2(IM is imidazole) as it afforded high yields of desired products in less reaction time and in the presence of ethanol whereas other required long reaction time and non green solvent. All the derivatives were assessed for in vitro anti-microbial activity with MIC values in the range of 1.56–6.25 μM (Figure 15).
3.2.2 Synthesis of other organic molecules
Click chemistry has been used to synthesize biologically active hybrids of several synthetic organic molecules. In lieu of this, Sharova et al. [51] demonstrated click chemistry inspired phosphorylation of anabasine, camphor, and cytisine using Cu assisted 1,3-diploar cycloaddition reaction. Later on, Touj et al. [52] synthesized copper N-heterocyclic carbene (Cu-NHC) complexes using benzimidazolium salt as a catalyst. These complexes were further used for the synthesis of triazole derivatives (26) (Figure 16).
Figure 16.
Synthesis of triazole derivatives.
The reaction involved mild reaction conditions, water as a green solvent with low catalyst loading, no need of further purification which made the protocol eco-friendly. Bernard et al. [53] investigated a cost effective, and convenient click chemistry inspired synthesis of cyclooctyne (27) and trans-cyclooctene (28) using inexpensive Cu powder as a catalyst (Figure 17).
Figure 17.
Synthesis of cyclooctyne and trans-cyclooctene.
Qui et al. [54] synthesized parthenolide–thiazolidinedione (29) hybrids using click chemistry-mediated coupling. The compounds were screened for anti-proliferative activity against prostate (PC3), breast (MDA-MB-231), and human erythroleukemia cell line (HEL) by MTT assay. The compound (29f) having 3,5-dimethoxyphenyl group exhibited the highest inhibitory effect against HEL (IC50 = 2.99 ± 0.22 μM), MDAMB-231 (IC50 = 2.07 ± 0.19 μM), and PC3 (IC50 = 3.09 ± 0.20 μM) (Figure 18).
Figure 18.
Synthesis of parthenolide–thiazolidinedione and 3’-O-1,2,3-triazolyl-guanosine-5′-o-monophosphate derivatives.
Senthilvelan et al. [55] designed synthesis of 3’-O-1,2,3-triazolyl-guanosine-5′-o-monophosphate (30) from in situ generation of azide from the resultant bromide followed by copper and β-cyclodextrin catalyzed cyclo-addition with 3′-O-propargyl guanosine monophosphate in aqueous media. The designed pathway has high regioselectivity and gave good yield of products (Figure 18).
3.3 Metal-free approach for click reaction
Several new metal-free click chemistry assisted syntheses of heterocyclic scaffolds have been designed up to date. These pathways involve a variety of functional group tolerance in the substrate of cyclo-addition reaction. These synthetic pathways can be achieved under mild conditions and give high yields of desired products using organo-catalyst [56, 57]. In 2010, Fokin and co-authors developed the first transition metal-free synthesis of 1,5-diaryl-1,2,3-triazoles (31) employing azide-alkyne cyclo-addition [58] (Figure 19Method 1). In this reaction, tetraalkylammonium hydroxide was used as the catalyst that provided moderate to high yield of products. Later on, in 2013, Ramachary and co-workers [59] achieved a region-selective synthesis of N-arylbenzotriazoles at room temperature using a cyclic enone and an arylazide under pyrrolidine catalysis at room temperature. Additional aromatization by DDQ gave fused heterocyclic scaffolds (32) (Figure 19Method 2). In the subsequent year, a one-pot tandem, Knoevenagel/azide-alkyne cycloaddition reaction between indole, aromatic aldehydes or pyrazole and phenylazide was fruitfully accomplished in the presence of piperidinium acetate in methanol to furnish the desired triazole derivatives (33) (Figure 19Method 3) [60].
Figure 19.
Metal-free synthetic route of triazole based heterocycles.
In 2018, Han et al. [61] developed a metal-free and solvent-free approach for the synthesis of 4-trifluroacetyl 1,2,3-triazoles in good yields with great selectivity. The synthesized compounds were examined for the anti-cancer activity and compound 34b possessed superior activity as compared to others against HePG2 (0.0267 μmol/mL) (Figure 20).
Figure 20.
4-Trifluroacetyl 1,2,3-triazole derivatives.
In the same year, Tan et al. [62] used thiol-ene click chemistry for the controlled functionalization of poly vinylidene fluoride in the presence of a base. The mechanism of the reaction suggests that it involves addition reaction followed by both Markonikov and anti-Markonikov mechanism and furnishes the same product. Later on in 2019, Moore and co-workers [63] designed a novel methodology for the synthesis of ionic liquids which were based on fluoroalkynyl imidazolium using thio-ene/yne click chemistry. The pathway has high conversion efficiency and high yields with no need for further purification.
3.4 Visible light assisted click chemistry
Visible-light-assisted organic transformations have received a huge response in chemical synthesis in order to design environmentally friendly approaches. The synthesis using economical, easily available visible-light sources have become vanguard in the synthetic chemistry as a prevailing approach for the activation of small molecules to furnish the desired products [64, 65, 66].
Burykina et al. [67] synthesized different kinds of vinyl sulphides (35) in high yields with good selectivity using thiol-yne click reaction using visible light. The designed pathway is transition-metal-free and gave Markonvikov-type product through a radical photo-redox pathway (Figure 21Method 1).
Figure 21.
Visible light assisted synthesis of vinyl sulphide.
Recently, Wu et al. [68] synthesized triazole analogs (36) through photo-redox electron-transfer mechanism. The authors inspected the reaction of benzyl azide with phenylacetylene using diverse photo-catalysts under ambient reaction conditions like room temperature (RT), air, and visible light irradiation. The catalyst (piq)2Ir(acac) or TPPT-Cl catalyzed the formation of triazole derivatives. The designed pathway is high region-selective, high yielding, having a high atom economy, and using solar catalysis (Figure 21Method 2).
3.5 Ultrasound assisted click chemistry
Ultrasound assisted reactions are milder and faster. The mechanism of ultrasound is based on an acoustic cavitation phenomenon. This technology hastens the reaction in both heterogeneous and homogeneous media, due to amplified energy intake. It shortens the reaction time and augments the competence of the system by triggering the catalyst surface area and removing deposited impurities [69, 70]. A decades ago, Cintas et al. [71] depicted the synthesis of 1,4- disubstituted 1,2,3-triazole analogs using Cu under ultrasound irradiation exclusive of a ligand. Later on, a heterogeneous catalytic system, Cu(II) doped clay was used at RT with ultrasonic irradiations [72]. The use of heterogeneous catalyst evaded needless complexity due to copper (I) salt redox protocol that involved the presence of ligands and protecting agents. The reaction is eco-friendly, easy to prepare, and recoverable. One-pot synthesis of 1,4-disubstituted-1,2,3-triazoles was successfully achieved using a benzyl or alkyl halide, sodium azide, and a terminal alkyne under these conditions [73]. The formation of triazole starting from a TMS protected alkynylglycoside was also demonstrated under ultrasound conditions with in situ deprotection of TMS group [74]. In 2020, Kritchenkov et al. synthesized triazole chitin derivatives and used them in the synthesis of Pd(II) complexes. Initially, ultrasound-assisted interaction of chitin with 1-azido-3-chloropropan-2-ol gave azido chitin and was further converted to triazole derivatives (37) that were used as ligands for the complex formation (Figure 22) [75].
Figure 22.
Synthesis of ultrasound assisted 1-azido-3-chloropropan-2-ol azido chitin derivatives.
3.6 Microwave-assisted click chemistry
The use of microwave irradiation in cyclo-addition reactions for click chemistry has also been comprehensively deliberated. It allows efficient internal heat transfer and therefore decreases the reaction time as well as enhances the reaction rate with high yield [76, 77]. The increased temperature can be used over short periods thus avoiding decomposition or polymerization. Ashok and co-workers demonstrated the synthesis of 1,2,3-triazole analogs using microwave irradiations in 8–10 min and examined their antimicrobial activity [78] (Figure 23Method 1). This method has also been applied in the preparation of 1,2,3-triazole analogs of nucleosides [79] (Figure 23Method 2). In general, those reactions which require prolonged conventional heating are accomplished in just 10–15 min using microwave irradiation. A chronological one pot Ru catalyzed cycloaddition was also designed from primary aryl or aliphatic bromides (Figure 23Method 3) [80].
Figure 23.
Microwave assisted synthesis of triazole based scaffolds.
4. Click chemistry in polymer synthesis
In the past two decades, various polymers have been introduced through ionene synthesis, click chemistry, and Michael addition via polycondensation and polyaddition process. Click chemistry reactions are known as reliable, powerful, high-yielding, and selective for the synthesis of novel and combinatorial compounds via Diels Alder cyclo-additions, copper-catalyzed azide-alkyne cycloadditions (CuAAC), and azide nitrile cycloadditions process [81, 82]. In 2013, Pasini reviewed the utility of click reaction for the efficient synthesis of macrocyclic structures like polymers, bio-conjugates, and dendrimers in different contexts [83]. Recently, Arslan and Tasdelen systematically reviewed the applications of click chemistry in polymer design and synthesis, and studies based on their architecture like block, cyclic, star, hyperbranched, and graftbrush comb polymers [84].
In 2018, Acik and co-authors demonstrated a simple copper (I)-catalyzed azide-alkyne cyclo-addition “click” reaction for the synthesis of polypropylene-graft-poly(L-lactide) copolymers (PP-g-PLAs) using different feeding ratio of alkyne end-functionalized poly(L-lactide) azide and side-chain functionalized polypropylene in the presence of CuBr/PMDETA and CuAAC [85]. This polymer exhibited special characteristics like good thermal property, wettability and biodegradability.
Öztürk and companions introduced efficient click chemistry inspired synthesis of an amphiphilic copolymer (41) from the reaction of propargyl-PEG and terminally azidepoly(ε-caprolactone) in CHCl3 at ambient temperature (Figure 24) [86]. This method displayed a synergistic arrangement of hydrophilic PEG and crystalline PCL to furnish novel materials with good applicability.
Figure 24.
Poly(CL-co-EG)star-type amphiphilic coploymer.
Yang et al. synthesized poly(3-hexylthiophene)-multiwalled carbon nanotube (P3HT-MWCNT) hybrid materials from in-situ click chemistry using Cu(I) / DBU catalytic system [87]. This novel hybrid also termed as organic–inorganic donor-acceptor material displayed special characteristics such as better thermal stability, higher melting point of 243.2 °C, good solubility, and optical properties.
Wang et al. reported a novel and efficient method for the synthesis of amphiphilic star-like rod-coil block copolymer poly(acrylic acid)-blockpoly(3-hexylthiophene) through the combined effect of atom transfer radical polymerization, quasi-living Grignard metathesis method, and thiol–ene click reaction to furnish narrow molecular weight distribution and well-defined molecular structures [88].
Agrihari et al. introduced CuAAC catalyzed synthesis of p-tert-butylcalix[4]arene linked benzotriazolyl dendrimers using CuSO4.5H2O and NaN3 to prepare N-1, N-2 type 6 fold compounds in good yields [89]. The synthesized compounds were evaluated for in vitro and in vivo anti-bacterial studies against a range of microbes and demonstrated good biological potential. Chen and his companions devised superhydrophobic cotton fabric from mercaptan and vinyl trimethoxysilane using ultraviolet irradiation via thiol-ene click chemistry [90]. This fabric possesses special characteristics like economic, highly resistant towards acids, acetone, UV light, water, and other liquids.
Henning et al. utilized copper-catalyzed azide/alkyne cycloaddition reaction for the efficient synthesis of triazole-based photo-initiators (42) for the two-photon polymerization process (Figure 25) [91]. Here Me-Mono and Ph-Mono initiators displayed higher tolerability and sensitivity in microfabrication areas.
Figure 25.
Synthesis of triazole-based photo-initiators.
A novel, facile and efficient synthesis of 3- and 4-arm star-shaped poly(2-methyl-N-aziridine)s (43, 44) from ring opening reaction of N-sulfonyl aziridines in the presence of trimethylsilylazide and PMDETA (N,N,N′,N″,N″-pentamethyldiethylenetriamine) through click reaction with CuBr and alkyne was demonstrated by Luo et al. (Figure 26) [92].
Cai et al. presented a one-step click chemistry process for the synthesis of high performance graphene oxide/ styrene-butadiene rubber (GO/SBR) composites using pentaerythritoltetra(3-mercapto propionate) [93]. Experiments and molecular simulation results concluded that these composites displayed upgraded gas permeability, thermal conductivity, dynamic, and static mechanical performances.
Tian and companions demonstrated the synthesis of the functionalized poly(1-butene)(45)via sequential thiol-ene click reaction and ring-opening polymerization using poly(1,3-butadiene) as a substrate (Figure 27) [94]. Here C═C bond was further functionalized from thiol-ene reaction using hydroxyl-containing thiol compounds.
Figure 27.
Functionalized poly(1-butene) synthesis.
Zhang et al. devised synthesis of thiol-maleimide ‘click’ chemistry based β-cyclodextrin polymers in an aqueous medium without generating by-products [95]. The structure of products was affected by temperature range i.e. higher temperature gave higher molecular weighted and compact structures. The obtained polymers showed better dissolution performance and drug complex-forming capacity as compared to the parental structure.
Gao et al. reported thiol-ene click reactions in polysulfide oligomers and acrylate monomers to prepare processable and self-healable thermosets and elastomers (46)via different pathways like photo-initiator, redox-initiator system and base mediated catalytic approaches (Figure 28) [96]. Reprocessable and self-healable properties depend upon polymer structure and their synthetic methodology, therefore, DBU based catalytic synthesis displayed better activity as compared to other processes, due to their catalytic efficiency for disulfide bond exchanges.
Figure 28.
Process able and self-healable polymer synthesis.
Zhu et al. introduced facile click chemistry assisted poly(2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl methacrylate) graphene oxide composite (PTMA-GO) (47) assisted reaction in ambient conditions and utilized them as cathode materials (Figure 29) [97]. After completing 300 charge–discharge cycles,the specific capacity was found to be 2.3 times higher for this composite as compared to the PTMA electrode.
Figure 29.
PTMA-GO polymer synthesis.
Shen et al. devised synthesis of superhydrophilic and superoleophobic PEGylated PAN membrane (48) from poly (ethylene glycol) methyl ether methacrylate (PEGMA) monomers via thiol-ene click chemistry (Figure 30) [98]. After this fabrication, pore size of the membrane was reduced and displayed low flux. The fabricated membrane exhibited excellent separation (99%) of various oil–water emulsion and fouling-resistant ability.
Figure 30.
PEGylated PAN membranes.
5. Conclusion
Synthetic organic chemistry includes the synthesis of biologically active molecules and designing of potent scaffolds. Click chemistry is one of the toolboxes for chemistry, biology, nano, and material sciences. It has vivid applications in the synthesis of organic molecules, polymers, nanoparticles, biosensors, and many more. The concept of click chemistry fulfills the green aspects of a reaction. In this chapter, we have deliberated an incredible flurry of activities in the field of click chemistry inspired synthesis. This study highlights the current advancements in the synthesis of heterocyclic and other cyclic structures using click reactions. The insertion of a triazole ring with the help of click reaction increases the biological activity of the synthesized compounds. Different pathways with metal or metal-free conditions using conventional or non-conventional reaction methods have also been demonstrated in this chapter.
Acknowledgments
The authors are grateful to the Department of Chemistry, Mohan Lal Sukhadia University, Udaipur (Raj.), India for providing necessary library facilities for carrying out the work. A. Sethiya is thankful to UGC-MANF (201819MANF-2018-2019-RAJ-91971) for providing Senior Research Fellowship to carry out this work. N. Sahiba is very much grateful to CSIR-Delhi (file no. 09/172(0088)2018-EMR-I), New Delhi for providing Senior Research Fellowship as a financial support.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"click chemistry, organic synthesis, eco-benign synthesis, selectivity, atom economy, cyclo-addition",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75328.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75328.xml",downloadPdfUrl:"/chapter/pdf-download/75328",previewPdfUrl:"/chapter/pdf-preview/75328",totalDownloads:496,totalViews:0,totalCrossrefCites:2,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:63,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"December 26th 2020",dateReviewed:"January 22nd 2021",datePrePublished:"February 18th 2021",datePublished:"September 1st 2021",dateFinished:"February 18th 2021",readingETA:"0",abstract:"Click chemistry involves highly efficient organic reactions of two or more highly functionalized chemical entities under eco-benign conditions for the synthesis of different heterocycles. Several organic reactions such as nucleophilic ring-opening reactions, cyclo-additions, nucleophilic addition reactions, thiol-ene reactions, Diels Alder reactions, etc. are included in click reactions. These reactions have very important features i.e. high functional group tolerance, formation of a single product, high atom economy, high yielding, no need for column purification, etc. It also possesses several applications in drug discovery, supramolecular chemistry, material science, nanotechnology, etc. Being highly significant and valuable, we have elaborated on several aspects of click reactions in organic synthesis in this chapter. Recent advancements in the field of organic synthesis using click chemistry approach have been deliberated by citing last five years articles.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75328",risUrl:"/chapter/ris/75328",book:{id:"10507",slug:"current-topics-in-chirality-from-chemistry-to-biology"},signatures:"Ayushi Sethiya, Nusrat Sahiba and Shikha Agarwal",authors:[{id:"337057",title:"Assistant Prof.",name:"Shikha",middleName:null,surname:"Agarwal",fullName:"Shikha Agarwal",slug:"shikha-agarwal",email:"shikhaagarwal@mlsu.ac.in",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Mohanlal Sukhadia University",institutionURL:null,country:{name:"India"}}},{id:"345237",title:"Ms.",name:"Ayushi",middleName:null,surname:"Sethiya",fullName:"Ayushi Sethiya",slug:"ayushi-sethiya",email:"ayushisethiya92@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"345238",title:"Ms.",name:"Nusrat",middleName:null,surname:"Sahiba",fullName:"Nusrat Sahiba",slug:"nusrat-sahiba",email:"sahibanusrat786@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Green aspects of click reactions",level:"1"},{id:"sec_3",title:"3. Role of click reactions in synthetic chemistry",level:"1"},{id:"sec_3_2",title:"3.1 Classification of click reaction",level:"2"},{id:"sec_4_2",title:"3.2 Metal-catalyzed approach for the click synthesis",level:"2"},{id:"sec_4_3",title:"3.2.1 Synthesis of triazole derivatives",level:"3"},{id:"sec_4_4",title:"3.2.1.1 Metal-catalyzed synthesis of triazole derivatives",level:"4"},{id:"sec_5_4",title:"3.2.1.2 Metal Nano-particle based triazole synthesis",level:"4"},{id:"sec_7_3",title:"3.2.2 Synthesis of other organic molecules",level:"3"},{id:"sec_9_2",title:"3.3 Metal-free approach for click reaction",level:"2"},{id:"sec_10_2",title:"3.4 Visible light assisted click chemistry",level:"2"},{id:"sec_11_2",title:"3.5 Ultrasound assisted click chemistry",level:"2"},{id:"sec_12_2",title:"3.6 Microwave-assisted click chemistry",level:"2"},{id:"sec_14",title:"4. Click chemistry in polymer synthesis",level:"1"},{id:"sec_15",title:"5. Conclusion",level:"1"},{id:"sec_16",title:"Acknowledgments",level:"1"},{id:"sec_19",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Balasubramanian G, Balasubramanian KK. Applications of click chemistry in drug discovery and development. In: Click reactions in organic synthesis. Wiley;2016. DOI.10.1002/9783527694174'},{id:"B2",body:'Hein D, Liu X-M, Wang D. Click chemistry, a powerful tool for pharmaceutical sciences. Christopher Pharm Res. 2008;25(10):2216–2230. DOI: 10.1007/s11095-008-9616-1.'},{id:"B3",body:'Hou J, Liu X, Shen J, Zhao G, Wang PG. The impact of click chemistry in medicinal chemistry. Expert Opin Drug Discov. 2012;489–501. DOI: 10.1517/17460441.2012.682725.'},{id:"B4",body:'Lauwaet T, Miyamoto Y, Le SIC, Kalisiak J, Korthals KA, Ghassemian M, Smith DK, Sharpless KB, Fokin VV, Eckmann L. Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis. PLOS Negl Trop Dis. 14(4):e0008224. https://doi.org/10.1371/journal.pntd.0008224'},{id:"B5",body:'Li P-Z, Wang X-J, Zhao Y. Click chemistry as a versatile reaction for construction and modification of metal-organic frameworks. Coord Chem Rev. 2019;380:484–518.'},{id:"B6",body:'Tarnowska M. Krawczyk T. Click chemistry as a tool in biosensing systems for sensitive copper detection. Biosens Bioelectron. 2020;169:112614'},{id:"B7",body:'Li S, Zhou J, Huang YH, Roy J, Zhou N, Yum K, Sun X, Tang L. Injectable click chemistry-based bioadhesives for accelerated wound closure. ActaBiomater. 2020;110:95–104.'},{id:"B8",body:'Ouyang T, Liu X, Ouyang H, Ren L. Recent trends in click chemistry as a promising technology for virus-related research. Virus Res. 2018;256:21–28.'},{id:"B9",body:'Huang C-J. Advanced surface modification technologies for biosensors. In: Chemical, gas, and biosensors for the internet of things and related applications. Elsevier;2019. p. 65–86. DOI.org/10.1016/B978-0-12-815409-0.00005-X'},{id:"B10",body:'Fang-Ling Z, Si-Yu G, Yuan-Dong X, Jin-Ming Z, Yi L, Ning L. Applications of click chemistry reaction for proteomics analysis. Chinese J Anal Chem. 2020;48(4):431–438.'},{id:"B11",body:'Meyer JP, Adumeau P, Lewis JS, Zeglis BM. Click chemistry and radiochemistry: The first 10 years. Bioconjug Chem. 2016;27(12):2791–2807.'},{id:"B12",body:'Kenry. Bio-orthogonal click chemistry for in vivo bioimaging. Trends Chem. 2019;1(8):763–778.'},{id:"B13",body:'Yang H, Sukamtoh E, Du H, Wang W, Ando M, Kwakwaa YN, Zhang J, Zhang G. Click chemistry approach to characterize curcumin-protein interactions in vitro and in vivo. J Nutr Biochem. 2019;68:1-6. DOI.org/10.1016/j.jnutbio.2019.02.010.'},{id:"B14",body:'Binder WH, Sachsenhofer R. Click’ chemistry in polymer and materials science. Macromole Rapid Commun. 2007;28(1):15–54. https://doi.org/10.1002/marc.200600625.'},{id:"B15",body:'Moses JE, Moorhouse AD. The growing applications of click chemistry, ChemSoc Rev. 2007;36(8):1249–1262.'},{id:"B16",body:'Hanson J. John Cornforth(1917–2013). Nature. 2014;506:35.'},{id:"B17",body:'Shirame SP, Bhosale RB. Green approach in click chemistry. InTech Open. 2018. http://dx.doi.org/10.5772/intechopen.72928.'},{id:"B18",body:'Kolb HC, Finn MG, Sharpless KB. Click chemistry: Diverse chemical function from a few good reactions. Angew Chem Int Ed. 2001;40:2004–2021.'},{id:"B19",body:'Chandrasekaran S, Ramapanicker R. Click chemistry route to the synthesis of unusual amino acids, peptides, triazole-fused heterocycles and pseudodisaccharides. Chem Rec. 2017;17(1):63–70. DOI: 10.1002/tcr.201600093.'},{id:"B20",body:'Michinobu T, ÅoisDiederich F. The [2+2] cycloaddition-retroelectrocyclization (ca-re) click reaction: Facile access to molecular and polymeric push-pull chromophores. Angew Chem Int Ed. 2018;57:2–28.'},{id:"B21",body:'Totobenazara J, Burke AJ. New click-chemistry methods for 1,2,3-triazoles synthesis: Recent advances and applications. Tetrahedron Lett. 2015;56(22):2853–2859. Doi: http://dx.doi.org/10.1016/j.tetlet.2015.03.136'},{id:"B22",body:'Meldal M, Diness F. Recent fascinating aspects of the CuAAC click reaction. Trends Chem. 2020,2(6):569–584. https://doi.org/10.1016/j.trechm.2020.03.007.'},{id:"B23",body:'Heravi MM, Zadsirjan V, Dehghani M, Ahmadi T. Towards click chemistry: Multicomponent reactions via combinations of name reactions. Tetrahedron 2018;74:3391–3457.'},{id:"B24",body:'Huisgen R. 1,3-Dipolar cycloadditions. Past and future. Angew Chem Int Ed Engl. 1963;2:565–598.'},{id:"B25",body:'Wang C, Ikhlef D, Kahlal S, Saillard J-Y, Astruc D. Metal-catalyzed azide-alkyne “click” reactions: Mechanistic overview and recent trends. Coord. Chem. Rev. 2016;316:1–20.'},{id:"B26",body:'Johansson JR, Beke-Somfai T, Stalsmeden AS, Kann. Ruthenium-catalyzed azide alkyne cycloaddition reaction: scope, mechanism, and applications. Chem. Rev. 2016;116(23):14726–14768.'},{id:"B27",body:'Meng X, Xu XY, Gao TT, Chen B. Zn/C-catalyzed cycloaddition of azides and aryl alkynes. Eur. J. Org. Chem. 2010;5409–5414.'},{id:"B28",body:'McNulty J, Keskar K, Vemula R. The first well-defined silver(i)-complex-catalyzed cycloaddition of azides onto terminal alkynes at room temperature. Chem. Eur. J. 2011;17:14727–14730.'},{id:"B29",body:'Kim UB, Jung DJ, Jeon HJ, Rathwell K, Lee SG. Synergistic dual transition metal catalysis. Chem. Rev. 2020;120(24):13382–13433.'},{id:"B30",body:'Tăbăcaru A, Furdui B, Ghinea IO, Cârâc G, Dinică RM. Advances in click chemistry reactions mediated by transition metal based systems. InorganicaChimicaActa. 2017;455(2):329–349.'},{id:"B31",body:'Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. A stepwise huisgen cycloaddition process: Copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew Chem Int Ed. 2002;41:2596–2599.'},{id:"B32",body:'Guo H, Yanga F, Zhanga Y, Di XD. Facile synthesis of mono- and polytopicβ-cyclodextrin aromatic aldehydes by click chemistry. Synth Commun. 2014;45(3):338–347. doi.org/10.1080/00397911.2014.963400.'},{id:"B33",body:'Kumar S. Design and synthesis of 2′-d.eoxy-2′-[(1,2,3)triazol-1-yl]uridines using click chemistry approach. Nucleosides, Nucleotides, Nucleic Acids, 2015,34(5):371–378. DOI: 10.1080/15257770.2014.1003652.'},{id:"B34",body:'Tale RH, Gopula VB, Toradmal GK. “Click” ligand for “Click” chemistry: (1-(4-Methoxybenzyl)-1-H-1, 2, 3-triazol-4-yl) methanol (MBHTM) accelerated copper-catalyzed [3+2] azide-alkyne cycloaddition (CuAAC) at low catalyst loading. Tetrahedron Lett. 2015; http://dx.doi.org/10.1016/j.tetlet.2015.09.010.'},{id:"B35",body:'Shamala D, Shivashankara K, Chandra, Mahendra M. Synthesis of N1 and N2 coumarin substituted 1,2,3-triazole isomers via click chemistry approach. Synth Commun. 2016;46(5):433–441. doi.org/10.1080/00397911.2016.1140785'},{id:"B36",body:'Yarlagadda B, Devunuri N, Mandava VBR. Facile synthesis of n-(benzyl-1h-1,2,3-triazol-5-yl) methyl)-4-(6-methoxybenzo [d] thiazol-2-yl)-2-nitrobenzamides via click chemistry. J Heterocycl Chem. 2017;54(2):864–870.'},{id:"B37",body:'Anand A, Kulkarni MV. Click chemistry approach for the regioselective synthesis of iso-indoline-1,3-dione-linked 1,4 and 1,5 coumarinyl 1,2,3-triazoles and their photophysical properties. Synth Commun. 2017;47(7): 722–733.'},{id:"B38",body:'Anandhan R, Kannan A, Rajakumar P. Synthesis and anti-inflammatory activity of triazole-based macrocyclic amides through click chemistry. Synth Commun. 2017;47(7):671–679. DOI: 10.1080/00397911.2016.1254800.'},{id:"B39",body:'Lia J, Chen D, Zhang D, Wang Y, Yu Y, Gao L, Huang M. Preparation of triazole compounds via click chemistry reaction and formation of the protective self-assembled membrane against copper corrosion. Colloids and Surfaces A. 2018; 550:145–154.'},{id:"B40",body:'Kumar H, Savanur M, Naik KN, Ganapathi SM, Kim KM, Kalkhambkar RG. Click chemistry inspired design, synthesis and molecular docking studies of coumarin, quinolinone linked 1,2,3-triazoles as promising anti-microbial agents. ChemistrySelect 2018;3:5296–5303.'},{id:"B41",body:'Yarovaya O, Artyushin OI, Moiseeva AA, Zarubaev VV, Slita AV, Galochkina AV, Muryleva AA, Borisevich SS, Salakhutdinov NF, Brel VK. Synthesis of camphecene and cytisine conjugates using click chemistry methodology and study of their antiviral activity. Chem Biodiver. 2019;16(11):e1900340. DOI.10.1002/cbdv.201900340'},{id:"B42",body:'Khanapurmath N, Kulkarnia MV, Joshi S.D., Kumar G.N.A. A click chemistry approach for the synthesis of cyclic ureido tethered coumarinyl and 1-aza coumarinyl 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis H37Rv and their in silico studies. Bioorg Med Chem. 2019;27:115054.'},{id:"B43",body:'Chetia M, Gehlot PS, Kumar A, Sarma D. A recyclable/reusable hydrotalcite supported copper nano catalyst for 1,4-disubstituted-1,2,3-triazole synthesis via click chemistry approach. Tetrahedron Lett. 2018;59:397–401.'},{id:"B44",body:'Poshala S, Thung S, Manchala S, Kokatla HP. In situ generation of copper nanoparticles by rongalite and their use as catalyst for click chemistry in water. ChemistrySelect 2018;3:13759–13764.'},{id:"B45",body:'Chavana PV, Desai UV, Wadgaonkar PP, Tapase SR, Kodam KM, Choudhari A, Sarkar D. Click chemistry based multicomponent approach in the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles as potential anticancer agents. Bioorg Chem. 2019;85:475–486.'},{id:"B46",body:'Elavarasan S, Bhaumik A, Sasidharan M. An efficient Cu-mesoporous organic nanorod for Frieldländer quinoline synthesis, and click reactions. Chem Cat Chem. 2019;11(17):4350–4350. DOI: 10.1002/cctc.201900860.'},{id:"B47",body:'Gholampour M, Ranjbar S, Edrakic N, Mohabbatic M, Firuzi O, Khoshneviszadeh M. Click chemistry-assisted synthesis of novel aminonaphthoquinone-1,2,3-triazole hybrids and investigation of their cytotoxicity and cancer cell cycle alterations. Bioorg Chem. 2019;88: 102967.'},{id:"B48",body:'Khalili D, Rezaee M. Impregnated copper ferrite on mesoporous graphitic carbon nitride: An efficient and reusable catalyst for promoting ligand-free click synthesis of diverse 1,2,3-triazoles and tetrazoles. Appl Organo Metal Chem. 2019;e5219. https://doi.org/10.1002/aoc.5219'},{id:"B49",body:'Pourmohammad N, Heravi MM, Ahmadi S, Hosseinnejad T. In situ preparation and characterization of novel CuI-functionalized poly[(methyl methacrylate)-co-maleimide] as an efficient heterogeneous catalyst in the regioselective synthesis of 1,2,3-triazoles via click reaction: Experimental and computational chemistry. Appl Organo Metal Chem. 2019;33(7):e4967.'},{id:"B50",body:'Than ND, Hai DS, Bich VTN, Hien PTTH, Duyen NTD, Mai NT, Dung TT et al. Efficient click chemistry towards novel 1H-1,2,3-triazole-tethered 4Hchromene D-glucose conjugates: Design, synthesis and evaluation of in vitro antibacterial, MRSA and antifungal activities. Eur J Med Chem. 2019; 167: 454–471.'},{id:"B51",body:'Sharova EV, Genkina GK, Vinogradova NM, Artyushin OI, Yarovaya OI, Brel VK, Phosphorylation of natural products—Cytisine, anabasine, and camphor using click chemistry methodology. Phosphorus Sulfur and Silicon Relat Elem 2016;191(11–12):1556–1557. DOI: 10.1080/10426507.2016.1213257'},{id:"B52",body:'Touj N, Özdemir I, Yaşar S, Hamdi N. An efficient (NHC) Copper (I)-catalyst for azide–alkyne cycloaddition reactions for the synthesis of 1,2,3-trisubstituted triazoles: click chemistry. Inorg Chim Acta 2017;467:21–32.doi: http://dx.doi.org/10.1016/j.ica.2017.06.065'},{id:"B53",body:'Bernard S, Kumar RA, Porte K, Thuery P, Taran F, Audisio D. A practical synthesis of valuable strained eight-membered-ring derivatives for click chemistry. Eur J Org Chem. 2018;2000–2008. 10.1002/ejoc.201800139.'},{id:"B54",body:'Qiu J, Yuan C-M, Wen M, Li Y-N, Chen J, Jian J-Y, Huang L-J, Gu W, Li YM, Hao X-J. Design, synthesis, and cytotoxic activities of novel hybrids of parthenolide and thiazolidinedione via click chemistry. J Asian Nat Prod Res. 2020;22(5):425–433. DOI: 10.1080/10286020.2019.1597055'},{id:"B55",body:'Senthilvelan A, Shanmugasundaram M, Kore AR. An efficient synthesis of 3′-O-triazole modified guanosine-5′-O-monophosphate using click chemistry. Nucleosides, Nucleotides, Nucleic Acids 2019;38(6):418–427. DOI: 10.1080/15257770.2018.1554223.'},{id:"B56",body:'Becer CR, Hoogenboom R, Schubert US. click chemistry beyond metal-catalyzed cycloaddition. Angew. Chem. Int. Ed. 2009;48:4900–4908. DOI: 10.1002/anie.200900755.'},{id:"B57",body:'Dervaux B, Du Prez FE. Heterogeneousazide–alkyne click chemistry: Towards metal-free end Products. Chem. Sci. 2012;3:959–966. DOI: 10.1039/c2sc00848c.'},{id:"B58",body:'Kwok WS, Fotsing RJ, Fraser JR, Rodionov OV, Fokin VV. Transition-metal-free catalytic synthesis of 1,5-diaryl-1,2,3-triazoles. Org Lett. 2010; 12:4217–4219.'},{id:"B59",body:'Ramachary DB, Shashank BA. Organocatalytictriazole formation, followed by oxidative aromatization: Regioselective metal-free synthesis of benzotriazoles. ChemEur J. 2013;19:13175–13181.'},{id:"B60",body:'Maurya RA, Adiyala PR, Chandrasekhar D, Reddy CN, Kapure JS, Kamal A. Rapid access to novel 1,2,3-triazolo-heterocyclic scaffolds via tandem knoevenagel condensation/azide–alkyne 1,3-dipolar cycloaddition reaction in one pot. ACS Comb Sci. 2014;16:466–477.'},{id:"B61",body:'Han J, Ran J-X, Chen X-P, Wang Z-H, Wu F-H. Study on the green click-chemistry synthesis of 4-trifluoroacetyl-1,2,3-triazoles. Tetrahedron 2018; 74:6985–6992.'},{id:"B62",body:'Tan S, Li D, Zhang Y, Niu Z, Zhang Z. Base catalyzed thiol–ene click chemistry toward inner -CH=CF-bonds for controlled functionalization of Poly(vinylidene fluoride). Macromol Chem Phys. 2018;1700632, DOI: 10.1002/macp.201700632.'},{id:"B63",body:'Moore LMJ, Greeson KT, Redeker ND et al. Fluoroalkylfunctional imidazoles and imidazolium–based ionic liquids prepared via thiol-ene/yne click chemistry. J Mol Liq. 2019;295:111677. https://doi.org/10.1016/j.molliq.2019.111677.'},{id:"B64",body:'Liu Q, Wu L-Z. Recent advances in visible-light-driven organic reactions. Natl Sci Rev. 2017;4(3):359–380.https://doi.org/10.1093/nsr/nwx039'},{id:"B65",body:'Yu X-Y, Chen J-R, Xiao W-J. Visible light-driven radical-mediated c–c bond cleavage/functionalization in organic synthesis. Chem. Rev. 2020, https://doi.org/10.1021/acs.chemrev.0c00030'},{id:"B66",body:'Jagan MR, Narayanama, Stephenson CRJ. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 2011;40:102–113.'},{id:"B67",body:'Burykina JV, Shlapakov NS, Gordeev EG, BurkhardK¨onig, Ananikov VP. Selectivity control in thiol–yne click reactions via visible light induced associative electron upconversion. Chem Sci. 2020;11:10061–10070.'},{id:"B68",body:'Wu Z-G, Liao X-J, Yuan L, Wang Y, Zheng Y-X, Zuo J-L, Pan Y. Visible-light-mediated click chemistry for highly regioselective azide-alkyne cycloaddition via photoredox electron-transfer strategy. Chem Eur J. 2020;26(25):5694–5700. 10.1002/chem.202000252.'},{id:"B69",body:'BaigRBN, Varma RS. Alternative energy input: Mechanochemical, microwave and ultrasound-assisted organic synthesis. Chem. Soc. Rev. 2012;41:1559–1584.'},{id:"B70",body:'Banerjee B. Recent developments on ultrasound-assisted one-pot multicomponent synthesis of biologically relevant heterocycles. Ultrason Sonochem 2017;35:15–35.'},{id:"B71",body:'Cravotto G, Fokin VV, Garella D, Binello A, Boffa L, Barge A. Ultrasound-promoted copper-catalyzed azide−alkyne cycloaddition. J Comb Chem. 2010;12(1):13–15.'},{id:"B72",body:'Cintas P, Barge A, Tagliapietra S, Boffa L, Cravotto G.Alkyne–azide click reaction catalyzed by metallic copper under ultrasound. Nature Protocols 2010;5:607–616.'},{id:"B73",body:'Dar BA, Bhowmik A, Sharma A, Sharma PR, Lazar A, Singh AP, Sharma, M, Singh B. Ultrasound promoted efficient and green protocol for the expeditious synthesis of 1, 4 disubstituted 1, 2, 3-triazoles using Cu(II) doped clay as catalyst. Appl Clay Sci. 2013; 80–81: 351–357.'},{id:"B74",body:'Stefani HA, Silva NCS, Manarin F, Lüdtke DS, Zukerman-Schpector J. Madureira LS, Tiekink ERT. Synthesis of 1,2,3-triazolylpyranosides through click chemistry reaction. Tetrahedron Lett. 2012;53(14):1742–1747.'},{id:"B75",body:'Kritchenkova AS, Kletskov AV, Egorov AR, Kurasova MN, Tskhovrebov AG, Khrustalev VN. Ultrasound and click chemistry lead to a new chitin chelator. Its Pd(II) complex is a recyclable catalyst for the Sonogashira reaction in water. Carbohydr Polym. 2021;252:117167.'},{id:"B76",body:'Gupta AK, Singh N, Singh KN. Microwave assisted organic synthesis: Cross coupling and multicomponent reactions. Curr Org Chem. 2013;17(5). DOI : 10.2174/1385272811317050005'},{id:"B77",body:'Sharma N, Sharma UK, Van der Eycken EV. Microwave-assisted organic synthesis: overview of recent applications. In: Zhang W, Cue BW. Green techniques for organic synthesis and medicinal chemistry, 2nd Ed. Wiley; 2018.https://doi.org/10.1002/9781119288152.ch17,'},{id:"B78",body:'Ashok D, Gandhi DM, Srinivas G, Kumar V. Microwave-assisted synthesis of novel 1,2,3-triazole derivatives and their antimicrobial activity. Med Chem Res. 2014;23:3005–3018.'},{id:"B79",body:'Głowacka IE, Balzarini J, Wróblewski AE. Synthesis and biological evaluation of novel 1,2,3-triazolonucleotides. Arch Pharm Chem Life Sci. 2013;346:278–291.'},{id:"B80",body:'Johansson JR, Lincoln P, Nordén B, Kann N. Sequential one-pot ruthenium-catalyzed azide−alkyne cycloaddition from primary alkyl halides and sodium azide. J Org Chem. 2011;76(7):2355–2359.'},{id:"B81",body:'Zhang M, June SM, Long TE, Kong J. Principles of step-growth polymerization (polycondensation and polyaddition). In: Polymer Science: A comprehensive reference, 10 Volume Set. Vol. 5. Elsevier; 2011. p. 7–47. DOI: 10.1016/B978-0-12-803581-8.01410-7'},{id:"B82",body:'Milanese C. Chapter 5. Cycloaddition reactions in material science. In: Quadrelli P, editors. Modern applications of cycloaddition chemistry. Elsevier; 2019. p. 269. DOI: https://doi.org/10.1016/B978-0-12-815273-7.00005-8'},{id:"B83",body:'Pasini D. The click reaction as an efficient tool for the construction of macrocyclic structures. Molecules 2013;18:9512–9530. DOI: 10.3390/molecules18089512'},{id:"B84",body:'Arslan M, Tasdelen MA. Click chemistry in macromolecular design: Complex architectures from functional polymers. Chemistry Africa. 2019; 2:195–214. DOI: https://doi.org/10.1007/s42250-018-0030-8'},{id:"B85",body:'AcikG,AltinkokC,Tasdelen MA. Synthesis and characterization of polypropylene-graft-poly(L-Lactide) copolymers by CuAAC click chemistry. J Polym Sci Part A: Polym Chem. 2018;56(22):2595–2601.'},{id:"B86",body:'Öztürk T, Kılıçlıoğlu A, Savaş B, Hazer B. Synthesis and characterization of poly(ɛ-caprolactone-co-ethylene glycol) star-type amphiphilic copolymers by “click” chemistry and ring-opening polymerization. J MacromolSci A. 2018;55(8):588–594. DOI: 10.1080/10601325.2018.1481344'},{id:"B87",body:'Yang Z, Yu J, Fu K, Tang F. Preparation and characterization of poly (3- hexylthiophene) / carbon nanotubes hybrid material via in-situ click chemistry. Mater Chem Phys. 2018;223:797–804. DOI: https://doi.org/10.1016/j.matchemphys.2018.11.050.'},{id:"B88",body:'Wang X, Zhao C, Li Y, Lin Z, Xu H. A Facile and highly efficient route to amphiphilic star-like rod-coil block copolymer via a combination of atom transfer radical polymerization with thiol–ene click chemistry. Macromol Rapid Commun. 2020;1900540.'},{id:"B89",body:'Agrihari AK, Singh M, Singh AS, Singh AK, Yadav S, Maji P, Rajkhowa S, Prakash P, TiwariVK.Click inspired synthesis of p-tert-butyl calix[4]arenetetheredbenzotriazolyl dendrimers and their evaluation asanti-bacterial and anti-biofilm agents. New J Chem. 2020;44:19300–19313. DOI: 10.1039/D0NJ02591G'},{id:"B90",body:'Chen X, Chu R, Xing T, Chen G. One-step preparation of superhydrophobic cotton fabric based on thiol-ene click chemistry. Colloid Surface A. 2020;125803. DOI: https://doi.org/10.1016/j.colsurfa.2020.125803'},{id:"B91",body:'Henning I, Woodward AW, Rance JA, Paul BT, Wildman RD, Irvine DJ, Moore JC. A click chemistry strategy for the synthesis of efficient photoinitiators for two-photon polymerization. Adv Funct Mater. 2020;2006108.'},{id:"B92",body:'Luo W, Wang Y, Jin Y, Zhang Z, Wu C. One-pot tandem ring-opening polymerization of N-sulfonyl aziridines and “click” chemistry to produce well-defined star-shaped polyaziridines. J Polym Sci. 2020;1–10. DOI: 10.1002/pol.20200154'},{id:"B93",body:'Cai F, You G, Luo K, Zhang H, Zhao X, Wu S. Click chemistry modified graphene oxide/styrene-butadiene rubber composites and molecular simulation study. Compos Sci Technol. 2020;190:108061.'},{id:"B94",body:'Tian L, Gu J, Zhang H, Dong B. Preparation of functionalized poly(1-butene) from 1,2-polybutadiene via sequential thiol-ene click reaction and ring-opening polymerization. RSC Adv. 2020;10:42799–42803.'},{id:"B95",body:'Zhang M, Wei X, Xu X, Jin Z, Wang J. Synthesis and characterization of water-soluble β-cyclodextrin polymers via thiol-maleimide ‘click’ chemistry. Eur Polym J. 2020;128:109603. DOI: 10.1016/j.eurpolymj.2020.109603'},{id:"B96",body:'Gao H, Sun Y, Wang M, Wu B, Han G, Jin L, Zhang K, Xia Y. Self-healable and reprocessable acrylate-based elastomers with exchangeable disulfide crosslinks by thiol-ene click chemistry. Polymer, 2020;123132. https://doi.org/10.1016/j.polymer.2020.123132.'},{id:"B97",body:'Zhu J, Zhu T, Tuo H, Yan M, Zhang W, Zhang G, Yang X. TEMPO-contained polymer grafted onto graphene oxide via click chemistry as cathode materials for organic battery. Macromol Chemb Phys. 2020;2000160. DOI: 10.1002/macp.202000160'},{id:"B98",body:'Shen X, Liu P, He C, Xia S, Liu J, Cheng F, Suo H, Zhao Y, Chen L. Surface PEGylation of polyacrylonitrile membrane via thiol-ene click chemistry for efficient separation of oil-in-water emulsions. Sep Purif Technol. 2021;255:117418.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Ayushi Sethiya",address:null,affiliation:'
Synthetic Organic Chemistry Laboratory, Department of Chemistry, MLSU, Udaipur, India
Synthetic Organic Chemistry Laboratory, Department of Chemistry, MLSU, Udaipur, India
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1. Introduction
During cell division, proper chromosome segregation must be achieved to avoid unequal distribution of chromosomes to daughter cells. Spindle microtubules must attach to a single region of each chromosome, termed the “centromere,” in most eukaryotes. The kinetochore is a complex of proteins that are located at the centromere. Defects in the centromere-kinetochore and spindle check point functions lead to aneuploidy and cancer and are often associated with a poor prognosis. Therefore, it is highly important to study the spatiotemporal regulation and the structures of centromere and kinetochore proteins to understand chromosome instability (CIN) during development and cancer progression. The key question is how the chromosomal location and function of a centromere (i.e., centromere identity) are determined and thus participate in accurate chromosome segregation. In most species with regional centromeres (see the previous chapter for an exception of the budding yeast Saccharomyces cerevisiae that has genetically defined point centromeres), centromere identity relies not on a defined DNA sequence, but on the presence of a special nucleosome that contains a specific histone-like protein called CENP-A. CENP-A is proposed to be the non-DNA indicator (epigenetic mark) of centromere identity. CENP-A partially replaces histone H3 in the centromeric regions. CENP-A-containing nucleosomes are the basis for kinetochore formation and are the most important marker for centromere function in eukaryotes [1].
The structure of CENP-A-containing nucleosomes is more compact than H3-containing nucleosomes [2, 3, 4]. Although it is commonly reported that CENP-A-containing nucleosomes are formed with the canonical histones H2A, H2B, and H4 at the active centromeres, their structure remains controversial among different research groups [5]. CENP-A is at the top of a hierarchy of the pathway that determines the assembly of kinetochore components [6], and how CENP-A defines the position of the centromere in humans is the fundamental question. While the function of CENP-A protein is highly conserved among most eukaryotes, its protein sequence has apparently undergone both convergent and divergent evolution [7], and the centromere DNA repeats with which the CENPA-containing nucleosome interacts are also highly diverged. The architectures of CENP-A chromatin with quantified numbers of CENP-A (CenH3) molecules (e.g., ~400 molecules of human CENP-A/kinetochore) have been reported using fluorescence microscope assays among different species [8, 9, 10, 11]. CENP-A is also called CenH3 (centromere-specific histone H3). Its homologs in different species are summarized in Table 1.
Species
CENP-A homolog
E3 ligase (ubiquitylation or sumoylation)
Function
Preceding PTMs before ubiquitylation or sumoylation
Another proposed factor relevant to the E3 function
Saccharomyces pombe
Cnp1/SpCENP-A
N.D.
Proteasomal degradation to remove non-centromeric Cnp1
N.D.
N-terminal domain of Cnp1, Overexpression of H3/H4
Drosophila melanogaster
CID/Cid
CUL3/RDX (ubiquitylation)
Interacts with CAL3 and promotes CAL3 function, loading and stabilizing (maintenance) of CID protein at centromeres (proteasomal independent mechanism)
N.D.
N.D.
SCFPpa (ubiquitylation)
Prevents the promiscuous incorporation of CID across chromatin during replication, (targeting CID that is not in complex with CAL1)
S20 phosphorylation
S20 phosphorylation
APC/CCdh1 (ubiquitylation)
Degradation of the CAL1-CID complex (likely regulates centromeric CID deposition)
N.D.
N.D.
Homo sapiens
CENP-A
CUL4A/RBX1/COPS8
Facilitate interaction of CENP-A with HJURP through CENP-A ubiquitylation, CENP-A deposition at the centromere (proteasomal independent mechanism)
N.D.
COPS8 as an adaptor, heterodimerization of CENP-A, SUGT1-HSP90
Arabidopsis thaliana (CENH3 was expressed in Nicotiana tabacum)
AtCENH3
N.D. (VHHGFP4-human SPOP as synthetic E3 ligase expressed in Nicotiana tabacum)
Proteasomal degradation of AtCENH3
N.D.
N.D.
Table 1.
E3 ligases for CENP-A in species with regional centromeres.
Note: E3s of some species (e.g., Caenorhabditis elegans, Xenopus laevis, zebrafish Danio rerio, chicken Gallus domesticus DT40 cells, Mus musculus, etc.) are not discovered, and so are not described in this table. N.D. = not determined; PTMs = post-translational modifications.
CENP-A contains a short centromere targeting domain (CATD) within the histone fold region [2] in the C-terminus. Replacement of the corresponding region of histone H3 with the CATD is sufficient to direct histone H3 to the centromere [2], and this chimeric histone can rescue the viability of CENP-A-depleted cells [2, 12]. The CENP-A C-terminus contains another tail domain that recruits CENP-C to promote centromere and kinetochore assembly [13, 14]. CENP-N was also identified as the first protein to selectively bind CENP-A nucleosomes but not H3 nucleosomes during centromere assembly [15].
Meanwhile, the functions of the N-terminal CENP-A are also reported for some species [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27] (see also previous chapter, Sections 2.1, 2.2.2, 2.4.1, 2.9 and this chapter, Sections 2.1, 2.3, 2.4, 3.1, 4.1, 4.6, and 5.1). Loading of CENP-A at centromeres and its incorporation/deposition and maintenance in centromeric chromatin is cell cycle-regulated. In cells overexpressing CENP-A, the ectopic protein incorporates throughout the chromatin in interphase [28]. By the next G1, however, mis-incorporated CENP-A seems to have been cleared from chromatin by a mechanism that likely involves ubiquitin-mediated proteolysis, as suggested by experiments in yeast and Drosophila cells [28]. Importantly, the timing of deposition of newly synthesized CENP-A within the cell cycle may be variable not only among different species but also different developmental stages within the same species. Yeast suppressor of chromosome missegregation protein 3 (Scm3) [29] (previous chapter, Figure 1; Table 1) is a distant counterpart of human Holliday junction recognition protein (HJURP) (Figures 2 and 3; Table 1), and they are CENP-A (CenH3)-specific chromatin assembly factors [29, 41, 42, 43]. The incorporation of newly synthesized CenH3 (CENP-A) into centromeric nucleosomes depends on Scm3/HJURP [41, 42, 43] in budding, fission yeasts, and humans. In addition, other components and factors that contribute to CENP-A deposition, maintenance, and inheritance in centromeric nucleosomes have been reported [28, 44].
Figure 1.
Mechanistic scheme for Drosophila melanogaster CENP-ACID pathways. (Right) (a) Bade et al. proposed the role of the E3 ligase CUL3/RDX in CUL1-dependent ubiquitylation of CID [30, 31]. CUL3/RDX activity, which is presumably in dimer form [30], leads to the monoubiquitylation of CID through an interaction with the RDX-binding sites (RBS) of CAL1. This monoubiquitylation of CID is proteasomal-independent but is required for stable localization of CID and CAL1 to the centromere. The ubiquitin-conjugating enzyme (E2) bound on RBX1 is omitted for simplicity. (b) In the absence of RDX, CENP-A is not monoubiquitylated by CUL3, and both CENP-A and CAL1 are subjected to proteasome-dependent degradation, but presumably ubiquitylated by (c) SCFPpa or (d) APC/CCdh1 as Moreno-Moreno proposed [32] (see below). Furthermore, the absence of RDX results in cell death and severe chromosomal aberration (e.g., chromosome fragmentation), some of which may be attributed to the loss of CENP-A and CAL1 from centromeric regions (not shown in this cartoon). Moreno-Moreno et al. suggest that (c) whereas SCFPpa targets the fraction of CID that is not in complex with CAL1, (d) APC/CCdh1 contributes to the degradation of the CAL1-CID complex and, thus, likely regulates centromeric CID deposition [32] as previously proposed [30]. Huang et al. proposed that phosphorylation of CID of serine 20 (S20) regulates both protein turn-over and centromere-specific loading [33] (see also left). The CID S20 phosphorylation renders CID a substrate for ubiquitylation by SCFPpa, thereby regulating the abundance of free pre-nucleosomal CID through subsequent proteasomal degradation (see also left (g)). (Left) (e) The role of DLP/DAXX in CID deposition into ectopic nucleosomes through CID ubiquitylation as proposed in a human cell model [34] has yet to be confirmed experimentally. (f) CTCF occlusion by the aberrant nucleosome of heterotypic tetramer consisting of CENP-A-H4 with H3.3-H4 as proposed in human cell models [34] has not been confirmed in D. melanogaster. (g) Huang et al. observed that CID S20 is phosphorylated by casein kinase II (CK2) not only insoluble but also chromatin-bound CID, and this phosphorylation also facilitates removal of CID from ectopic but not from centromeric sites in chromatin [33]. (h) Factors/components that stabilize ectopically incorporated CID and are required for neocentromere formation and its maintenance are not yet clear. The status of overall PTMs, including polyubiquitylation of CID, especially in the ectopic nucleosome, has yet to be elucidated.
Figure 2.
Mechanistic scheme for human CENP-A pathways. (Right) In normal conditions, CUL4A-RBX1-COPS8 E3 ligase activity is required for CENP-A mono- or di-ubiquitylation on lysine 124 (K124) and CENP-A centromere localization [35]. CENP-A K124 mono- or di-ubiquitylation is required for CENP-A’s interaction with the chromatin assembly factor HJURP and CENP-A deposition at the centromere. The CUL4A complex targets CENP-A through the adaptor COPS8/CSN8 that has WD40 motifs. In non-canonical CRL4 machinery, CUL4/RBX1/COPS8 may dimerize as a CUL4/DACAF1 complex [36, 37], but the dimerization unit remains unknown [31]. Here only the CUL4/RBX1/COPS8 monomer is shown for simplicity. Upstream, the SGT1-HSP90 complex is required for the composition of the CUL4A complex and recognition of COPS8 to target CENP-A. Therefore, the SGT1-HSP90 complex is also required for CENP-A ubiquitylation and localization of CENP-A to centromeres. “CA” refers to the CENP-A monomer. “Ace” refers to the putative acetylated lysine 124 (K124) previously reported by Bui et al. that is concurrent with the structural transitions of CENP-A-containing nucleosomes through the cell cycle [38]. Their computational modeling suggests that acetylation of K124 causes tightening of the histone core and hampers accessibility to its C-terminus, which in turn reduces CENP-C interaction [39] (not shown in this cartoon). However, its precise function and relationship with K124 ubiquitylation remain to be studied. (Left) When human CENP-A is overexpressed, CENP-A is incorporated into ectopic nucleosomes consisting of a heterotypic tetramer that contains CENP-A-H4 with H3.3-H4 [34]. This ectopic localization of this particle (aberrant nucleosome) depends on the H3.3 chaperone DAXX rather than the centromeric CENP-A-specific chaperone HJURP. (a) Post-translational modifications of human CENP-A, especially before recognition by DAXX and after incorporation into the ectopic nucleosome, have yet to be elucidated. (b) CTCF occlusion by the aberrant nucleosome of a heterotypic tetramer consisting of CENP-A-H4 with H3.3-H4 was also proposed in a human cell model [34], but specific DAXX localization on these CTCF sites under CENP-A overexpression has not been confirmed experimentally. (c) Factors/components that stabilize ectopically incorporated CENP-A and are required for neocentromere formation and its maintenance are not yet clear. In addition, the status of overall post-translational modifications, including polyubiquitylation of CENP-A, especially in the ectopic nucleosome, is unknown. (d) Currently, the proteolysis mechanism for mis-incorporated human CENP-A and its E3 ligase is not yet clear. Note that histone H4 and phosphorylation of human CENP-A are omitted for simplicity.
Figure 3.
Models of epigenetic inheritance of CENP-A ubiquitylation through heterodimerization. In the octamer model, two CENP-A dimers in one nucleosome are split/diluted between the two daughter centromere-DNA sequences, and one CENP-A molecule replaces with one H3 molecule or leaves a molecule-free space during the replication/S phase. HJURP (Holliday junction recognition protein) predominantly interacts with ubiquitylated, preassembled “old” CENP-A, which resides mostly in nucleosomes. A non-ubiquitylated newly synthesized (“new”) CENP-A monomer targets ubiquitylated centromeric CENP-A through preassembled HJURP. Note that histone H4 is omitted for simplicity. (a) New CENP-A is appropriately ubiquitylated in a heterodimerization-dependent manner (i.e., dimers of old CENP-A with new CENP-A). In this way, both ubiquitylation and the location of the centromere are inherited epigenetically. (b) If K124 ubiquitylation does not occur on new CENP-A, the non-ubiquitylated CENP-A nucleosome distributed during the S phase does not recruit HJURP to the centromere because the affinity of non-ubiquitylated new CENP-A to HJURP is low. Subsequently, this loss of localization of HJURP at the centromere leads to the lack of new CENP-A targeting to ubiquitylated centromeric CENP-A through HJURP, and eventually to the lack of new CENP-A deposition. This figure is partly adapted from Niikura et al. [40].
Recently, many post-translational modifications of CENP-A and their functions have been reported [45]. They revealed the importance of these changes in CENP-A deposition at centromeres, proteolysis/protein stability, and recruitment of the CCAN (constitutive centromere-associated network) proteins [45]. Thus, here we focus on E3 ligase activities (i.e., on ubiquitylation and sumoylation) of CENP-A and summarize these functions for each species with regional centromeres in the following sections.
2. E3 ligase for fission yeast (Schizosaccharomyces pombe) CENP-ACnp1 and its function
2.1 Overview of CENP-ACnp1
Fission yeast (Schizosaccharomyces pombe) centromeres consist of large (40–100 kb) inverted repeats that display heterochromatic features. Therefore, fission yeast provides a good model for higher eukaryotic centromeres. The mechanistic processes to establish centromeric chromatin of fission yeast and its structures have been reviewed [46, 47]. This section focuses on the E3 ligase(s) for fission yeast CENP-ACnp1 and its function through ubiquitylation, although endogenous E3 ligase for S. pombe CENP-ACnp1 is not yet identified and its specific regulation is still unclear.
In fission yeast, the recruitment of the CENP-A-specific chaperone to the centromere is an essential step in epigenetic inheritance. The fission yeast Scm3 could be functionally homologous to HJURP. It interacts with CENP-A, localizes to centromeres during most of the cell cycle (except in mitosis), and is required for CENP-A deposition [48, 49]. Sequence analysis revealed a shared common domain in Scm3 and HJURP proteins [29]. Dunleavy et al. identified another chaperone known as Sim3 (start independent of mitosis 3) in fission yeast [50, 51]. Sim3 is homologous to known histone binding proteins NASP (human) and N1/N2 (xenopus) and aligns with Hif1 (S. cerevisiae), defining the SHNi-TPR family [51]. Sim3 is distributed throughout the nucleoplasm, yet it associates with CENP-ACnp1 and also binds H3. It interacts also with non-chromosomal CENP-A and is required for its incorporation in S. pombe. These results are consistent with those in Arabidopsis thaliana [19] (see also Section 5.1). Sim3 also has been proposed to share some common roles with the histone chaperone Asf1, mutations in which cause a defect in overall chromatin structure [52, 53]. It has been suggested that Sim3 could function as an escort chaperone, handing off CENP-A to Scm3, a role that human HJURP may accomplish by itself [43, 48, 50].
Mis16 (human homologs of Mis16 are RbAp46 and RbAp48) and Mis18 (human homologs of Mis18 are Mis18α and Mis18β) are required for loading of newly synthesized Cnp1/CENP-A into centromeric chromatin [54, 55], but are absent from organisms with point centromeres [44] (see also previous chapter, Section 2.3.3 and this chapter, Sections 3.1 and 4.1). Mis16 and Mis18 are also required for the maintenance of the hypoacetylation of histone H4 specifically within the central domain of the centromere [55], and Mis16 homologs are components of several histone chaperon complexes [56]. Moreover, acetylation of histone H4 lysine 5 and 12 (H4K5ac and H4K12ac) within the pre-nucleosomal CENP-A-H4-HJURP complex mediated by the RbAp46/48-Hat1 complex is required for CENP-A deposition into centromeres in chicken and humans [57], consistent with Hat1’s role in Drosophila melanogaster [58] (see also Sections 3.1 and 4.1). In mouse studies, Mis18α interacts with DNMT3A/3B, and this interaction is required to maintain DNA methylation [59]. Mis18α deficiency leads to not only the reduction of DNA methylation, but altered histone H3 modifications, and uncontrolled noncoding transcripts in the centromere region (see also Section 4.1). It is an interesting model that Mis16 and Mis18 complexes “prime centromeres” affect post-translational modifications of histone H3/H4 proteins and centromeric DNA in advance of CENP-A incorporation. How such chromatin structures feedback with the regulation of E3 ligases of CENP-A has not yet been reported, which could be important.
In S. pombe, spMis16, and spMis18 mutants eliminate Cnp1 incorporation to centromeres and Mis18 directly interacts with Scm3 in vitro, suggesting they cooperate to assemble Cnp1 into centromeric chromatin [48]. S. pombe lacks the vertebrate Mis18BP1 ortholog, and the Mis18BP1 function in S. pombe is replaced by the Eic1 protein (a.k.a Mis19) [44, 60, 61]. While Eic2 (a.k.a Mis20) is dispensable for the recruitment of Cnp1 to the centromere, Eic1 is required for the recruitment of the Mis18, Mis16, and Scm3 proteins to the centromere and Cnp1 incorporation. Both of the Eic1 and Eic2 proteins co-purify with the spMis18 and exhibit a similar centromeric localization throughout the cell cycle [60, 61]. Taken together, these data suggest that Eic1 is functionally analogous to the Mis18BP1 subunit [60, 61]. However, Eic1 is evolutionarily distinct and no homolog of Mis19 has been found in the human genome, and Eic1 does not share any apparent sequence homology to Mis18BP1 [60, 61]. Centromere localization and function of Mis18 require Yippee-like domain-mediated oligomerization [62]. Furthermore, there are at least two mechanisms to restrict the assembly of CENP-A nucleosomes in G1—disruption of Mis18 multimerization by HJURP-Mis18 interaction, and ubiquitylation and degradation of Mis18β through SCFβTrCP E3 ligase [44].
Domain-specific function, such as the N-terminal function, of fission yeast Cnp1/CENP-A is also reported as budding yeast Cse4 [24, 25] (see also previous chapter, Section 2.4). Folco et al. demonstrated that alteration of the Cnp1 N-tail does not affect Cnp1 loading at centromeres, outer kinetochore recruitment, or spindle checkpoint signaling but significantly increases chromosome loss [17]. On the other hand, their N-tail mutants exhibit centromere inactivation enhanced by an altered centromere. The N-tail mutants specifically reduced localization of the CCAN proteins CENP-TCnp20 and CENP-IMis6, but not CENP-CCnp3. Therefore, these authors suggest that the Cnp1 N-tail maintains the epigenetic stability of centromeres in fission yeast, at least in part via assembly of the CENP-T branch of the CCAN. Tan et al. identified a proline-rich “GRANT” (Genomic stability Regulating site within CENP-A N-Terminus) motif that is essential for Cnp1 centromeric targeting [24]. They showed that especially GRANT proline-15 (P15) undergoes cis-trans isomerization to drive proper chromosome segregation. This cis-trans isomerization appears to be carried out by two FK506-binding protein (FKBP) family prolyl cis-trans isomerases. In addition, they identified Sim3 as a Cnp1 NTD interacting protein that is dependent on GRANT proline residues. Together, they suggest cis-trans proline isomerization of Cnp1 is required for precise propagation of centromeric integrity in fission yeast, presumably via targeting Cnp1 to the centromere. Thus, the requirement of cis-trans proline isomerization of CenH3Cnp1 in fission yeast studies appears to be consistent with the one of CenH3Cse4 proposed in budding yeast studies [63] (see also previous chapter, Section 2.2.3). However, they suggest that the GRANT-prolines of Cnp1 do not coordinate proteolysis of the SpCENP-A protein as do proline residues in the budding yeast Cse4 NTD. In addition, Tan et al. showed that sequential truncation of the NTD did not improve the stability of the protein, suggesting that the NTD of Cnp1 does not regulate the turnover of the protein [25]. Instead, they proposed that heterochromatin integrity may contribute to Cnp1 stability and promote its chromatin incorporation.
Compared to the studies of budding yeast and some of the other species, currently, there are few studies on post-translational modifications and domain-specific functions of fission yeast CenH3/Cnp1. Further research is required on the relationships among Cnp1 post-translational modifications, structural change, interaction with its chaperones (e.g., Scm3 and Sim3), and surrounding heterochromatin regulation.
2.2 Dos1/2-Cdc20 complex
In S. cerevisiae, all pre-existing CENP-A is replaced by newly synthesized CENP-A during the S phase [64], whereas in S. pombe, two pathways of CENP-A deposition exist at the S and G2 phases of the cell cycle [50, 65]. Parental CENP-A is deposited at centromeres during the S phase, whereas newly synthesized CENP-A is deposited during later stages of the cell cycle [66]. The mechanisms involved in the deposition of CENP-A at centromeres during the S phase remain poorly understood [66]. In S. pombe, the GATA-like transcription factor Ams2, a key factor in CENP-A deposition during the S phase, appears to work, at least in part, through the regulation of transcription of core histones [65].
Li et al. reported that the DNA polymerase (Pol) epsilon catalytic subunit A (pol2), Cdc20, interacts with the Dos1-Dos2 silencing complex to facilitate heterochromatin assembly and inheritance of H3K9 methylation during the S phase [67]. We note that fission yeast S. pombe Cdc20 (UniProtKB—P87154) is not the ortholog of human CDC20 (cell division cycle protein 20 homolog, UniProtKB—Q12834), but of human POLE (UniProtKB—Q07864). Gonzalez et al. showed that the Dos1/2-Cdc20 complex is also required for localization of Cnp1 at centromeres at this stage [66]. Disruption of Dos1 (also known as Raf1/Clr8/Cmc1), Dos2 (also known as Raf2/Clr7/Cmc2), or Cdc20, a DNA polymerase epsilon subunit, leads to delocalization of CENP-A from centromeres and mislocalization of the protein to ectopic (non-centromeric) sites. All three mutants of Dos1, Dos2, and Cdc20 exhibit spindle disorganization and mitotic defects. Inactivation of Dos1 or Cdc20 also results in the accumulation of noncoding RNA transcripts from centromeric cores, a feature common to mutants affecting kinetochore integrity. These authors found that Dos1 physically associates with Ams2 and contributes to the interaction of Ams2 with centromeric cores during the S phase. They further showed that Dos2 associates with centromeric cores during the S phase and that its recruitment to centromeric cores depends on Cdc20. Together, this study identifies a physical link between DNA replication and the CENP-A assembly machinery and provides mechanistic insight into how CENP-A is faithfully inherited during the S phase.
It is important to clarify how exactly the Dos1-Dos2-Cdc20 complex contributes to the inheritance of preexisting Cnp1 during centromere replication [66]. Interestingly, Rik1 is a component of silencing factors. The heterochromatic methylation of histone H3-K9 by Clr4 is promoted by silencing factors: Dos1-Dos2-Rik1-Lid2 [67]. Horn et al. reported that subunits of a cullin-dependent E3 ubiquitin ligase interact with Rik1 and Clr4, and Rik1-TAP preparations exhibit robust E3 ubiquitin ligase activity [68]. They also demonstrated that the expression of a dominant-negative allele of the Pcu4 cullin subunit (the human Cullin-4 homolog) disrupts the regulation of K4 methylation within heterochromatin. Hong et al. also reported a novel complex that associates with the Clr4 methyltransferase, termed the CLRC (CLr4-Rik1-Cul4) complex using affinity purification of Rik1, and found that Rik1 interacts with the fission yeast Cullin4 (Cul4, encoded by cul4+), the ubiquitin-like protein, Ned8, and two previously uncharacterized proteins, designated Cmc1 and Cmc2 [69]. They also demonstrated a defect in the processing of noncoding RNA to small RNA caused by the defective Clr4-Rik1-Cul4 complex, suggesting that the components of the Clr4-Rik1-Cul4 complex collaborate at an early step in heterochromatin formation. Unlike the studies of CUL3/RDX in fruit flies (Figure 1, right; see also Section 3), the function of Cul4 E3 ligase targeting non-centromeric CENP-ACnp1 and the mechanism of its proteolysis are not yet studied in fission yeast. In fission yeast, there is no report about the involvement of Cul4 E3 ligase in CENP-ACnp1 deposition at the centromere, unlike in humans (Figure 2, right; see also Section 4). On the other hand, it would be interesting to test if the Cul4 E3 function for heterochromatin assembly is conserved in other species, including humans.
2.3 Assembly of Cnp1 at non-centromeric chromatin
Consistent with the results in budding yeast Cse4 [23, 70, 71] (see also the previous chapter, Section 2.1), Gonzalez et al. reported that the overexpression of fission yeast Cnp1 results in the assembly of Cnp1 at non-centromeric chromatin during mitosis and meiosis [18]. The non-centromeric Cnp1 is preferentially recruited near heterochromatin and is able to recruit kinetochore components, and Cnp1 overexpression leads to severe chromosome missegregation and spindle microtubule disorganization. Moreover, ectopic Cnp1-containing chromatin is inherited over multiple generations using pulse induction of Cnp1 overexpression. Interestingly, ectopic assembly of Cnp1 is suppressed by overexpression of histone H3 or H4 (Table 1), as other groups suggest that the balance between histones H3 and H4 and CENP-A is important for centromeric chromatin assembly [72, 73]. Further, Gonzalez et al. demonstrated that deletion of the N-terminal domain of Cnp1 results in an increase in the number of ectopic CENP-A sites, suggesting that the N-terminal domain of CENP-A prevents CENP-A assembly at ectopic loci via the ubiquitin-dependent proteolysis [18].
However, it is not yet clear by which E3 ligase the exogenous Cse4 expressed in the fission yeast S. pombe is targeted, and a budding yeast Psh1 homolog is not yet identified in fission yeast. Further study is required to elucidate how the activity of a specific E3 ligase targeting endogenous Cnp1 is regulated in fission yeast.
2.4 Heterochromatin and RNAi regulate centromeres by protecting Cnp1 from ubiquitin-mediated degradation
In most eukaryotes, the centromere is flanked and bordered by the epigenetically distinct heterochromatin domain. The establishment of centromeric heterochromatin profoundly correlates to centromere function, but the precise role of heterochromatin in centromere specification and activation is not yet clear. The transition between point centromeres (e.g., budding yeast S. cerevisiae) and regional centromeres (e.g., fission yeast S. pombe) is considered one of the most substantial centromere evolutionary events.
Yang et al. demonstrated that budding yeast Cse4 can localize to centromeres in fission yeast and partially substitute fission yeast Cnp1, however, overexpressed Cse4 localizes to heterochromatin regions [26]. Cse4 undergoes efficient ubiquitin-dependent degradation in S. pombe, and its N-terminal domain contributes to its centromere distribution via ubiquitination. Importantly, their results showed that GFP-Cse4 fails to localize at centromeres without heterochromatin and RNA interference (RNAi) using Clr4 mutant (clr4Δ) and dicer mutant (dcr1Δ), respectively. Therefore, they showed that RNAi-dependent heterochromatin is required for centromeric localization of Cse4 and protects Cse4 from ubiquitin-dependent degradation. Heterochromatin is also required for the deposition of native Cnp1 at the centromere via the same mechanism. Together, they suggest that protection of CENP-A from degradation by heterochromatin is a conserved mechanism used for centromere assembly and provided novel insights into centromere evolution from point centromere to regional centromere.
However, E3 ligase targets endogenous Cnp1 is still unclear, and its degradation mechanism through heterochromatin and RNAi machinery in fission yeast is still elusive. Further study is required to elucidate how E3 ligase activity is involved in RNAi-dependent heterochromatin formation and maintenance in fission yeast.
3. E3 ligase for fruit fly (Drosophila melanogaster) CENP-ACID and its function
3.1 Overview of CENP-ACID
Fruit fly (Drosophila melanogaster) centromeres extend for 200–420 kb and contain repetitive DNA that is interspersed with transposable elements (TEs) [74]. TEs are sequences that have the capacity to move other chromosomal locations and are a component of the “interspersed repeat” fraction of most genomes [75]. In fruit flies and other species (e.g., plants, wallabies, humans), the significance and function of these TEs in centromeric DNA remain to be studied. In plants, Jiang et al. suggest that the retention of active transcriptional machinery within the long terminal repeat may promote demarcation of the active centromere [76] (see also Section 5). The importance of centromeric long noncoding RNA (cenRNA) for centromere integrity has been suggested in various species [77, 78, 79]. In humans, a cenRNA is required for targeting CENP-A to the centromere [80] (see also Section 6). Arunkumar and Melters hypothesize that loading of both CENP-A and CENP-C could be one major function of centromeric transcripts, and RNA-DNA triplexes (e.g., R-loops) could be involved in loading both proteins; thereby, one may elucidate the role of RNA-DNA triplexes in both CENP-A and CENP-C loading [77].
The mechanism of heterochromatin silencing in fruit flies has been reported [81], including the position-effect variegation [82], histone modification [83], and the RNAi machinery [84]. Recently, a PIWI-interacting RNAs (piRNAs) system has been implicated in heterochromatin formation [85, 86, 87, 88], and the mechanism of heterochromatic piRNA production is being elucidated in Drosophila [89]. Ectopic CID/the Drosophila CENP-A homolog is prone to localize at euchromatin-heterochromatin boundaries, and this observation suggests that CID chromatin is likely to localize right next to a heterochromatin domain [90]. Kwenda et al. showed that RNA polymerase I transcription is required for efficient CID assembly in meiosis, as well as centromere tethering to nucleoli [91]. Recent work in mammalian and fruit fly cell lines showed that chemical inhibition of activated RNA polymerase 2 (RNAP2) resulted in the loss of centromeric CID chromatin [80, 92]; and the elongation factor Spt6 facilitates maintenance of centromeric CID [93]. These reports strongly suggest that transcription and RNA production are involved in CID incorporation.
The timing of CID incorporation occurs during metaphase/anaphase in D. melanogaster [74]. In human cells, the incorporation of newly synthesized CENP-A occurs in telophase/early G1 [94, 95]. Similar to humans, in the fast cycles of Drosophila syncytial embryos, CID incorporates in anaphase [96]. However, in Drosophila Kc cells, GFP-tagged CID was detected in metaphase cells 2 h after induction of its expression, implying that incorporation occurred at some point between the preceding G2 and metaphase [97]. In S2 cells, newly synthesized CAL1 is deposited at centromeres in prophase, preceding CID loading in metaphase [98]. Based on this observation, CAL1, like the Mis18 complex in humans, was suggested to prime the centromere before assisting in CID loading [98, 99]. In somatic tissues of Drosophilalarvae, centromeric CID deposition initiates at late telophase and continues during G1 when APC/CCdh1 is active [32, 100].
In Drosophila, Erhardt et al. performed an RNAi-based genome-wide search and identified CAL1 and CENP-C for CID localization determinants [101]. CID, CAL1, and CENP-C co-immunoprecipitate and are mutually dependent for centromere targeting and function. However, the molecular mechanism underlying these dependencies remains to be clarified. No homologs for CAL1 have been reported in other organisms. They also proposed that the mitotic cyclin A (CYCA) localizes at the centromere, and CYCA and RCA1/Emi1 couple centromere assembly to the cell cycle through regulation of the fizzy-related/CDH1 subunit of the APC [101], while Moreno-Moreno et al. proposed that APC/CCdh1 contributes to the degradation of the CAL1-CID complex [32] (see also Section 3.3). Consistent with the role of histone H4 acetylation in chickens and humans [57], Boltengagen et al. showed that the histone acetyltransferase Hat1 contributes to the CID/CENP-A assembly pathway in D. melanogaster [58] (see also previous chapter, Section 2.3.3 and this chapter, Sections 2.1 and 4.1).
Recently, there have been more reports published on the mechanism of how these three proteins (CID, CAL1, and CENP-C) work in CID incorporation. Chen et al. showed that the constitutive centromere protein CENP-C is required for recruitment of the Drosophila melanogaster (mel) CAL1 protein to existing centromeres [102]. Rosin and Mellone showed that exogenously expressed CAL1 from two different Drosophila species was efficiently recruited to D. melanogaster endogenous centromeres [103]. The CENP-C interaction with CAL1 is conserved across the Drosophila phylogeny. Whereas the coordinated evolutionary changes between CAL1 and CID prevent the recruitment of Drosophila species bipectinata (bip) CID to melanogaster centromeres, the CAL1 proteins showed no species specificity in their recruitment. The importance of the CENP-C protein for recruiting the CENP-A deposition machinery is shared in the fly and human centromere assembly pathways. However, in humans, the Mis18 complex, which is absent in Drosophila, interacts with CENP-C to recruit HJURP and CENP-A to existing centromeres [104] (see also Section 4.1).
CENP-A is maintained to mark paternal centromeres, whereas most histones are removed from mature sperm. In Drosophila males, Kwenda et al. showed that the centromere assembly factors CAL1 and CENP-C are required for meiotic chromosome segregation, CID assembly and maintenance on sperm, and fertility [91]. They showed that CID accumulates with CAL1 in nucleoli in meiosis, and CENP-C normally limits the release of CAL1 and CID from nucleoli for proper centromere assembly in meiotic prophase I. Pauleau et al. found that overexpression of CAL1 is associated with increased CID levels at centromeres and uncouples CID loading from mitosis [105]. CID levels inversely correlate with mitosis, and mitosis length is influenced by the spindle assembly checkpoint. They found that CAL1 interacts with the SAC protein and RZZ complex component Zw10 and thus constitutes the anchor for the recruitment of RZZ. Demirdizen et al. showed that the N-terminus of CID contributes to nuclear localization and protein stability [106]. While co-expression of mutant CID with RbAp48 leads to exclusive non-centromeric CID incorporation, co-expression with CAL1 leads to exclusive centromere loading of CID, suggesting that CID-associated proteins, rather than CID itself, determine its localization. Their further analysis revealed that NuRD is required for ectopic CID incorporation. The interaction of the NuRD complex with CENP-A is mediated by RbAp48 and MTA1-like (i.e., a subunit of NuRD complex), which binds specifically to the N-terminal region of CENP-A. Roure et al. showed a positive feedback loop between CID, CENP-C, and CAL1 [107], and Medina-Pritchard et al. showed that CAL1 binds both CID and CENP-C without the requirement for the Mis18 complex, using X-ray crystallography [108].
Studies of the neocentromere have also been performed in Drosophila [109, 110, 111], and the requirements, mechanism, and transmission for the neocentromere are actively under study. Two groups independently reported overexpressed CID mislocalization and ectopic incorporation into non-centromeric chromatin [112, 113]. Heun et al. demonstrated that overexpressed CID is mislocalized into normally non-centromeric regions in Drosophila tissue culture cells (S2 cells) and animals and induces severe mitotic defects [113]. These CID mis-incorporated regions display the presence of microtubule motors and binding proteins, and spindle attachments. Moreno-Moreno et al. showed that centromeric localization of transiently expressed CID is impaired in the presence of the proteasome inhibitor MG132 in Kc cells, and mislocalization of CID affects cell cycle progression with strong mitotic defects [112]. Recently, Palladino et al. used a LacO/LacI ectopic centromeric chromatin assembly system and showed that multiple genomic locations can acquire centromere activity. In addition, they demonstrated that these de novo centromeres can be transmitted and maintained epigenetically in mitotic tissues [114]. Together, their data suggest that proteolysis-mediated regulation of ectopic CenH3CID is also present in fruit flies as in other species. Further mechanisms of CID protein degradation, including the identification of E3 ligase, are described in the following Sections 3.2 and 3.3.
3.2 CUL3/RDX E3 Ligase
In Drosophila, CENP-ACID deposition to centromeres depends on a specialized loading factor that is called CAL1 [30]. Bade et al. showed that CAL1 directly interacts with RDX, an adaptor for CUL3/RDX-mediated ubiquitylation, through the two conserved RDX-binding sites (RBSs) of CAL1 [30] (Figure 1a; Table 1). However, CAL1 is not a substrate of the CUL3/RDX ligase but functions as an additional substrate-specifying factor for the CUL3/RDX-mediated ubiquitylation of CID. It is noteworthy that this fly CID ubiquitylation is proteasomal independent—ubiquitylation of CID by CUL3/RDX does not trigger its degradation but stabilizes CID and CAL1. Loss of RDX leads to rapid degradation of CAL1 and CID and to massive chromosome segregation defects during development (Figure 1b). Therefore, they suggest a proteolysis-independent role of ubiquitin conjugation in centromere regulation that is essential for the maintenance of the centromere-defining protein CID and its loading factor CAL1. Bade et al. proposed that this CID ubiquitylation event induces a conformational change within the CAL1/CID complex, or alternatively, increases the affinity toward centromeric chromatin, where it is protected from proteasomal degradation. The data of Bade et al. support a dual role of CAL1 in both loading and stabilizing CID protein (Figure 1a). Interestingly, their proposed “proteasomal-independent” mechanism of CUL3/RDX-mediated fly CID ubiquitylation is consistent with one of CUL4-mediated human CENP-A ubiquitylation found independently by our group [35, 115, 116, 117] (Figure 2, right; Table 1; see also Section 4.2). In humans, our group speculates that CENP-A mono- or di-ubiquitylation might sterically affect the overall conformational change, L112 residue, or C-terminal portion of the CATD on which HJURP recognition is mainly dependent (see also Section 4.2).
In humans, ectopic localization of CID depends on the H3.3 chaperone DAXX rather than the centromeric CENP-A specific chaperone HJURP [34] (Figure 2, left). This human CENP-A-containing ectopic nucleosome involves a heterotypic tetramer that contains CENP-A-H4 with H3.3-H4 [34] (Figure 2, left). Cells overexpressing human CENP-A are more tolerant of DNA damage induced by camptothecin or ionizing radiation, and both the survival advantage and CTCF occlusion by the aberrant nucleosome of heterotypic tetramer in these human cells are dependent on DAXX [34] (Figure 2, left). Although D. melanogaster has a DAXX ortholog, Daxx-like protein (DLP), the role of DLP/DAXX in CID deposition into ectopic nucleosomes through CID ubiquitylation (Figure 1e) and the CTCF occlusion by the aberrant nucleosome (Figure 1f) must be confirmed experimentally in D. melanogaster.
3.3 The E3-ligases SCFPpa and APC/CCdh1 co-operate to regulate CID expression across the cell cycle
Moreno-Moreno et al. reported that the F box protein partner of paired (Ppa), which is a variable component of an SCF E3-ubiquitin ligase complex, controls CenH3CID stability in Drosophila [44, 118] (Figure 1b; Table 1). They showed that Ppa depletion results in increased CenH3CID levels, and Ppa physically interacts with CenH3CID through the CATDCID and regulates CenH3CID stability in Drosophila [44, 118]. Their results showed that most known SCF complexes are inactive at mitosis when newly synthesized CenH3CID is deposited at centromeres. Therefore, they suggest that CenH3CID deposition and proteolysis are synchronized events in Drosophila. They further reported that, in Drosophila, CID expression levels are regulated throughout the cell cycle by the combined action of SCFPpa and APC/CCdh1 [32] (Table 1). They showed that SCFPpa regulates CID expression in G1. Importantly, in S phase SCFPpa prevents the promiscuous incorporation of CID across chromatin during replication. In the G1 phase, CID expression is also controlled by APC/CCdh1. They also showed that CAL1, the specific chaperone that deposits CENP-ACID at centromeres, protects CID from SCFPpa-mediated degradation but not from APC/CCdh1-mediated degradation. Together, they suggest that, whereas SCFPpa targets the fraction of CID that is not in complex with CAL1 (Figure 1c; Table 1), APC/CCdh1 contributes to the degradation of the CAL1-CID complex and, thus, likely regulates centromeric CID deposition (Figure 1d; Table 1).
3.4 Phosphorylation of Drosophila CID on serine 20 regulates protein turnover and centromere-specific loading
Huang et al. showed that CID is phosphorylated at serine 20 (S20) by casein kinase II (CK2) and that the phosphorylated form is enriched on chromatin during mitosis [33] (Figure 1c and g; Table 1). Their results revealed that S20 phosphorylation regulates the turnover of prenucleosomal CID through the SCFPpa-proteasome pathway (Figure 1c; Table 1) and that phosphorylation facilitates removal of CID from ectopic but not from centromeric sites in chromatin (Figure 1g and h; Table 1). They provided multiple lines of evidence for an essential role of S20 phosphorylation in regulating restricted incorporation of CID into centromeric chromatin, suggesting that modulation of the phosphorylation state of S20 may lead to fine-tuned control of CID levels to prevent malignant incorporation into non-centromeric chromatin.
On the other hand, factors/components that stabilize ectopically incorporated CID and are required for neocentromere formation and its maintenance are not clear in D. melanogaster (Figure 1h). The status of overall post-translational modifications, including polyubiquitylation of CID, especially in ectopic nucleosomes, remains to be elucidated.
4. E3 ligase for human CENP-A its function
4.1 Overview of human CENP-A
In most eukaryotes, including humans, the centromere has no defined DNA sequence but is associated with large arrays of repetitive DNA; in humans, this sequence is a 171-bp alpha-satellite DNA, although several other sequence types are found in this region. CENP-A-containing nucleosomes are formed with canonical histones H2A, H2B, and H4 at the active centromeres [5]. CENP-A nucleosomes localize to the inner plate of mammalian kinetochores [119] and bind to the 171-bp alpha-satellite DNA. Recently, the importance of centromeric cis-element, transcription, and centromeric long noncoding RNA (cenRNA) for centromere integrity has been suggested in various species, including humans [77, 78, 79] (see also Sections 3 and 5). Interestingly, when the CENP-B box DNA sequence is located proximal to the CENP-A nucleosome, CENP-B forms a more stable complex with the CENP-A nucleosome through specific interactions with CENP-A [120]. In humans, a centromeric long noncoding RNA (cenRNA) is required for targeting CENP-A to the centromere [80].
Currently, it is commonly reported that CENP-A-containing nucleosomes are formed with canonical histones H2A, H2B, and H4 at the active centromeres, however, their structure remains controversial among different research groups [5]. Bui et al. suggest that CENP-A nucleosomes alter from tetramers to octamers before replication and revert to tetramers after replication, using combinatory methods, including atomic force microscopy [38]. It is noteworthy that reversible chaperone binding, chromatin fiber folding changes, and CENP-A K124 acetylation (K124ac) and H4 K79 acetylation (K79ac) are concurrent with these structural transitions. Further computational modeling suggests that acetylation of K124 causes tightening of the histone core and hampers accessibility to its C-terminus, which in turn reduces CENP-C interaction [39] (see also the following paragraph about the function of histone H4 acetylation). Further study, including the solution of real-time post-translational modifications or the 3D structure of free Cse4 complexes, is required to determine how different chaperons recognize Cse4/CENP-A-H4 for incorporation into different locations of chromatin.
CENP-A contains a short centromere targeting domain (CATD) within the histone fold region [2]. Replacement of the corresponding region of H3 with the CATD is sufficient to direct H3 to the centromere [2], and this chimeric histone can rescue the viability of CENP-A-depleted cells [2, 12]. On the other hand, Logsdon et al. found contributions from small portions of the N-terminal tail and the CATD in the initial recruitment of CENP-C and CENP-T, using a LacO/LacI ectopic centromeric chromatin assembly system [20]. Jing et al. reported that deletion of the first 53 but not the first 29 residues of CENP-A from the N-terminus, resulted in its cytoplasmic localization [121]. They identified two motifs for CENP-A nuclear accumulation and one motif involved in the centromeric accumulation of CENP-A, as well as the interaction of CENP-A with core histone H4 and CENP-B.
Early studies in human cells showed that CENP-A mRNA and protein start to accumulate in the mid-S phase and peak in G2 [122, 123], however, further cell type-specific regulation of human CENP-A mRNA and protein remains to be studied.
In human cells, the incorporation of newly synthesized CENP-A occurs in telophase/early G1 [94, 95]. The incorporation of newly synthesized CENP-A into centromeric nucleosomes depends on the HJURP, which is a CENP-A-specific chromatin assembly factor [41, 42, 43]. Like CENP-A, HJURP is also assembled during early G1 to centromeres [42, 43, 94, 96]. The primary structural analysis demonstrated that human HJURP is a distant counterpart of Scm3, which is required to deposit centromeric nucleosomes in yeast [29]. CENP-A interacts with HJURP as a soluble pre-nucleosomal complex, and the unique structural dynamics of HJURP together with CENP-A/H4 heterodimer/tetramer (pre-nucleosomal CENP-A-H4-HJURP complex) have been reported [3, 124, 125, 126, 127, 128, 129, 130, 131, 132]. HJURP recruitment to centromeres depends on the activity of the Mis18 complex [41, 104], which affects the histone modification and DNA methylation status of centromeres [54, 59]. The human proteins hMis18 and M18BP1/KNL2 are recruited to the centromere at telophase/G1, suggesting that the hMis18 complex and RbAp46/48 (homologs of Mis16) prime the centromere for CENP-A localization [54, 133]. Moreover, acetylation of histone H4 lysine 5 and 12 (H4K5ac and H4K12ac) within pre-nucleosomal CENP-A-H4-HJURP complex mediated by the RbAp46/48-Hat1 complex is required for CENP-A deposition into centromeres in chickens and humans [57], consistent with the role of Hat1 shown in D. melanogaster [58] (see also Section 3.1). In mouse studies, Mis18α interacts with DNMT3A/3B, and this interaction is required to maintain DNA methylation [59]. Mis18α deficiency leads to not only the reduction of DNA methylation, but altered histone H3 modifications, and uncontrolled noncoding transcripts in the centromere region. Faithful CENP-A deposition requires integrated signals from Plk1 and cyclin-dependent kinase (CDK), with Plk1 promoting the localization of the Mis18 complex, and CDK inhibiting Mis18 complex assembly [134]. Moreover, the remodeling and spacing factor complex is required for the assembly of CENP-A chromatin [135], and the CENP-A licensing factor M18BP1/KNL2 and the small GTPases-activating protein MgcRacGAP cooperate to maintain the stability of newly loaded CENP-A at centromeres [136, 137].
Currently, the proteolysis mechanism for mis-incorporated human CENP-A and its E3 ligase is not yet clear (Figure 2d), and there are no reports to date on proteasome-mediated degradation of human CENP-A [138]. We reported that mono- or di-ubiquitylation of CENP-A K124 is required for CENP-A deposition at the centromere [35] (Figure 2, right). However, the stability of endogenous CENP-A is not affected by CUL4A or RBX1 depletion, and the stability of exogenous CENP-A K124R is the same as in wild-type cells. Rather, overexpression of a monoubiquitin-fused CENP-A mutant induces neocentromere formation, suggesting that signaling CENP-A mono- or di-ubiquitylation determines centromere location and activity [115] (see also Sections 4.2 and 4.3). Future studies are required to reveal how ectopic CENP-A is degraded and removed from the non-centromeric chromosome, and/or how the neocentromere established through CENP-A ubiquitylation is deactivated in humans (Figure 2c and d). This proteolysis could be initiated on chromatin and the machinery involved could be specifically excluded from centromeric regions. Alternatively, mis-incorporated CENP-A nucleosomes may dissociate more easily than those properly localized and be subsequently degraded in the nucleoplasm [139]. Obuse et al. performed chromatin immunoprecipitation with an anti-CENP-A monoclonal antibody using HeLa interphase nuclei and systematic identification of its interactors by mass spectrometric analyses [140]. They identified UV-damaged DNA binding protein 1 (DDB1) as a component of the CEN complex and BMI-1 that is transiently co-localized with the centromeric region in interphase.
RbAp46 forms a complex with the CRL4 ubiquitin ligase and DDB1 protein (where DDB1 mediates the association of CUL4 with its substrate-specific receptor—RbAP46) [141, 142]. RbAp46 is required for stabilizing CENP-A protein levels and the CRL4-RbAp46 complex activity promotes efficient new CENP-A deposition in humans [142]. This is in contrast to studies in yeast and fruit flies, where the association of CENP-A with the SCF E3-ubiquitin ligase complex leads to CENP-A degradation. However, our group showed that CUL4A-RBX1-COPS8 E3 ligase activity is required for CENP-A mono- or di-ubiquitylation on lysine 124 (K124) and CENP-A centromere localization, although our results suggest that DDB1 is not required for CENP-A recruitment to centromeres [35] (Figure 2, right; see also Sections 4.2–4.5). In humans, soluble CENP-A is associated with the centromeric CENP-A specific chaperone HJURP (see also Introduction). Depletion of HJURP leads to a significant decrease in CENP-A levels, suggesting that HJURP protects the fraction of CENP-A that will be incorporated at the centromere in G1 while remaining “free” CENP-A will be degraded to prevent its incorporation into non-centromeric chromatin [42, 43]. Our results also support this model, because CENP-A ubiquitylation enhances the affinity between HJURP with ubiquitylated CENP-A [35] (see also Sections 4.2–4.5).
One question is also generated about the function of H3.3 histone chaperone proteins, HIRA and DAXX, which were previously reported to promote ectopic CENP-A deposition in human cancer cells [34, 143]. Lacoste et al. found that CENP-A overexpression in human cells leads to ectopic enrichment at sites of active histone turnover involving a heterotypic tetramer that contains CENP-A-H4 with H3.3-H4 [34] (Figure 2, left). Ectopic localization of this particle (aberrant nucleosome) depends on the H3.3 chaperone DAXX rather than the centromeric CENP-A specific chaperone HJURP (Figure 2, left). Cells overexpressing CENP-A are more tolerant of DNA damage induced by camptothecin or ionizing radiation, and both the survival advantage and CTCF occlusion by the aberrant nucleosome of heterotypic tetramer in these cells are dependent on DAXX (Figure 2, left). However, post-translational modifications of human CENP-A, especially before recognition by DAXX and after incorporation into the ectopic nucleosome, must be elucidated (Figure 2a), and specific DAXX localization on these CTCF sites under CENP-A overexpression has to be confirmed experimentally (Figure 2b).
Shrestha et al. showed that mislocalization of CENP-A to chromosome arms is one of the major contributors to CIN, as depletion of histone chaperone DAXX prevents CENP-A mislocalization and rescues the reduced interkinetochore distance and CIN phenotype in CENP-A-overexpressing cells [144]. Nye et al. reported that in human colon cancer cells, the H3.3 chaperones HIRA and DAXX promote ectopic CENP-A incorporation [143]. They found that a correct balance between levels of the centromeric chaperone HJURP and CENP-A is required to prevent ectopic assembly by H3.3 chaperones. Their results also suggest that CENP-A occupancy at the 8q24 locus is significantly correlated with amplification and overexpression of the MYC gene within that locus. Together, CENP-A mislocalization into non-centromeric regions resulting from its overexpression leads to chromosomal segregation aberrations and genome instability [145]. Overexpression of CENP-A is a feature of many cancers and is likely associated with malignant progression and poor outcomes [146, 147, 148]. CENP-A overexpression is often accompanied by overexpression of its chaperone HJURP, leading to “epigenetic addiction” in which increased levels of HJURP and CENP-A become necessary to support rapidly dividing p53-deficient cancer cells [149]. In addition, the functional roles of DAXX and HIRA in the development of cancer and other diseases have been described [150, 151, 152, 153]. Elucidation of the proper mechanism of H3.3 incorporation into chromatin through DAXX and HIRA may also lead to proper CENP-A incorporation at centromeres as well as an effective disease (e.g., cancer) therapy.
Recently, the importance of the site-specific posttranslational modifications of human CENP-A and their biological functions has been reported [44, 45]. The functional roles of phosphorylation at CENP-A-Ser68 are still under active investigation [124, 125, 154, 155, 156]. How the defects of CENP-A PTMs and the dysfunction of centromere contribute to the generation and the development of cancer is an unsolved question. Takada et al. demonstrated that CENP-A Ser18 hyperphosphorylation by cyclin E1/CDK2 occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to CIN [157]. This CENP-A Ser18 hyperphosphorylation reduced the CENP-A centromeric localization, increased CIN, and promoted anchorage-independent growth and xenograft tumor formation. Defects of CENP-A PTMs are significantly associated with chromosome segregation errors and CIN [149].
4.2 CENP-A K124 ubiquitylation is required for CENP-A deposition at the centromere
In budding yeast, Scm3 and Psh1 might compete for binding to Cse4. Cse4 that is not associated with Scm3 may be targeted by Psh1 for proteolysis, but Cse4 in a complex with Scm3 may be protected [71] (see also previous chapter, Section 2.1). On the other hand, in D. melanogaster it was proposed that CENP-ACID ubiquitylation induces a conformational change within the CAL1/CENP-A complex, or alternatively, increases the affinity toward centromeric chromatin, where it is protected from proteasomal degradation [30] (see also Section 3.2).
In humans, our group found that CUL4A-RBX1-COPS8 E3 ligase activity is required for CENP-A mono- or di-ubiquitylation on lysine 124 (K124) and CENP-A centromere localization [35] (Figure 2, right). CUL4A complex targets CENP-A through the adaptor COPS8/CSN8 that has WD40 motifs in non-canonical CRL4 machinery (Figure 2, right). A mutation of CENP-A, K124R, reduces interaction with HJURP and abrogates localization of CENP-A to the centromere. The addition of monoubiquitin is sufficient to restore CENP-A K124R to centromeres and the interaction with HJURP, indicating that “signaling” ubiquitylation is required for CENP-A loading at centromeres (Figure 2, right).
However, one question remains—how does such mono- or di-ubiquitylation of CENP-A facilitate the interaction of CENP-A with HJURP? The CENP-A K124 site and its proximal residues might not directly affect CENP-A-HJURP interaction in the crystal structure of the HJURP-CENP-A-histone H4 complex, since we did not detect defects in CENP-A dimerization of K124R mutant (Figure 3; see also Section 4.3) or any ubiquitin interacting motif in HJURP. Therefore, we speculate that CENP-A mono- or di-ubiquitylation might sterically affect the overall conformational change, L112 residue (the closest CENP-A’s residue to K124 out of the seven residues reported to be important for appropriate interaction with HJURP), or C-terminal portion of the CATD on which HJURP recognition is mainly dependent. In addition, acetylated lysine 124 (K124) was previously reported by Bui et al. [38], but the functional role of K124 acetylation and its relationship with K124 ubiquitylation remains to be studied (Figure 2, right). Moreover, currently, the proteolysis mechanism for mis-incorporated human CENP-A and its E3 ligase is not clear, and there are no reports to date regarding proteasome-mediated degradation of human CENP-A [138] (Figure 2d). Future studies are required to reveal how ectopic CENP-A is degraded and removed from the non-centromeric chromosome (Figure 2c and d).
4.3 CENP-A ubiquitylation is inherited through dimerization between cell divisions
The mechanism by which centromere inheritance occurs is largely unknown. Gassmann et al. suggested that in Caenorhabditis elegans, pre-existing CENP-AHCP−3 nucleosomes are not necessary to guide the recruitment of new CENP-A nucleosomes [158]. In contrast, in Drosophila melanogaster, CENP-ACID is present in mature sperm, and the amount of CID that is loaded during each cell cycle appears to be determined primarily by the pre-existing centromeric CID, a finding that is consistent with a “template-governed” mechanism [159]. However, in humans, it is unclear how CENP-A works as the epigenetic mark at the molecular level.
Our group showed that pre-existing ubiquitylated CENP-A is necessary for the recruitment of newly synthesized CENP-A to the centromere and that CENP-A ubiquitylation is inherited between cell divisions (Figure 3). In vivo and in vitro analyses using dimerization mutants and dimerization domain fusion mutants revealed that the inheritance of CENP-A ubiquitylation requires CENP-A dimerization. Therefore, we propose models in which CENP-A ubiquitylation is inherited and centromere location is determined through dimerization (Figure 3).
Numerous studies have found that CENP-A can be experimentally mistargeted to non-centromeric regions of chromatin and that this mistargeting leads to the formation of ectopic centromeres in model organisms [160]. Chromosome engineering has allowed the efficient isolation of neocentromeres on a wide range of both transcriptionally active and inactive sequences in chicken DT40 cells [57]. More than 100 neocentromeres in human clinical samples have been described [161]. They form on diverse DNA sequences and are associated with CENP-A localization, but not with alpha-satellite arrays; thus, these findings provide strong evidence that human centromeres result from sequence-independent epigenetic mechanisms. However, neocentromeres have not yet been created experimentally in humans; overexpression of CENP-A induces mislocalization of CENP-A, but not the formation of functional neocentromeres [162].
Our group demonstrated that overexpression of a monoubiquitin-fused CENP-A mutant induces neocentromeres at non-centromeric regions of chromosomes, and this result further supports our model in which CENP-A ubiquitylation is inherited and determines centromere location through dimerization (Figure 3). Our assay using the LacO/LacI ectopic centromeric chromatin assembly system clearly revealed that CENP-A ubiquitylation contributes to the recruitment of CENP-A chaperones (HJURP and DAXX) and outer kinetochore components (HEC1 and SKA1). It is possible that ubiquitylation of CENP-A contributes to maintain and stabilize ectopic neocentromeres in humans (Figure 2c).
However, it remains unclear how the neocentromere established through CENP-A ubiquitylation is deactivated. Future studies are required to reveal the mechanism of site-specific (centromeric and/or non-centromeric) deubiquitylation CENP-A and subsequent proteolysis in humans (Figure 2c and d). In this context, it would be interesting to test if the Ubp8-driven deubiquitylation mechanism in budding yeast [163] (see also previous chapter, Section 2.7) is conserved in humans.
4.4 SGT1-HSP90 complex is required for CENP-A loading at centromeres
The mechanism that controls the E3 ligase activity of the CUL4A-RBX1-COPS8 complex remains obscure. Our group found that the SGT1-HSP90 complex is required for recognition of CENP-A by COPS8 [164] (Figure 2, right). SGT1/SUGT1, a co-chaperone of HSP90, is involved in multiple cellular activities, including cullin E3 ubiquitin ligase activity [165]. The SGT1 gene was originally isolated as a dosage suppressor of the skp1–4 mutant in yeast S. cerevisiae, which causes defects in yeast kinetochore function, but also as a novel subunit of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex [166]. In both yeast and humans, the interaction between SGT1 and heat shock protein 90 (HSP90) is also required for kinetochore assembly [167, 168, 169]. In humans, cancer cells utilize Hsp90 as a chaperone to promote the folding and function of mutated or overexpressed oncoproteins, because aberrant oncoproteins are unstable [170, 171]. SGT1 contributes to cancer development by stabilizing oncoproteins, and the SGT1-HSP90 complex is a potential target for therapies aimed at cancer, brain, and heart disease [165].
Our group initially applied RNA interference (RNAi)-mediated SGT1 and/or HSP90 depletion in HeLa cells and found that the SGT1-HSP90 complex is required for CENP-A ubiquitylation in vivo and CENP-A deposition at centromeres [164] (Figure 2, right). Moreover, our group and others demonstrated in vivo interactions of SGT1A with CUL4A [164] and HSP90 with CUL4 [172], respectively (Figure 2, right). Previously, we had also reported that the CUL4A complex targets CENP-A through the adaptor COPS8/CSN8 that has WD40 motifs in non-canonical CRL4 machinery [35] (Figure 2, right; see also Section 4.2). Therefore, we hypothesized that depletion of SGT1 or HSP90 protein promotes loss of interaction among components of the CUL4A complex. Indeed, SGT1 or HSP90 siRNA disrupted interactions of COPS8 with CENP-A and CUL4A. These results suggest that the SGT1-HSP90 complex is required for the composition of the CUL4A complex as well as recognition of CENP-A by COPS8 (Figure 2, right). Thus, we clarified how the SGT1-HSP90 complex contributes to the E3 ligase activity of the CUL4A complex in CENP-A ubiquitylation (Figure 2, right).
In our study, SKP1 siRNA treatment did not lead to any signal reduction of CENP-A at centromeres [164]. Therefore, we proposed that the SGT1-HSP90 complex is involved in CENP-A deposition at centromeres in an SKP1-independent and/or SCF-independent manner. This conclusion is consistent with our previous report that the CUL4A-RBX1 complex, which does not require SKP1 to function, contributes to CENP-A deposition at centromeres [35]. Because our results suggest that SKP1 is not required for the recruitment of CENP-A to centromeres, it is unlikely that SKP1 activity affects the CENP-A loading pathway. Because CENP-A is at the top of a hierarchy of the pathway that determines the assembly of kinetochore components [6], destabilization of the MIS12 complex at the kinetochore was observed by Davies et al. [173] could be partially due to the defect in CENP-A recruitment. This idea is supported by our results demonstrating that SGT1 siRNA treatment did not significantly change the recruitment of endogenous MIS12, HEC1, and SKA1 proteins in LacO arrays after ectopic loci were determined through LacO-LacI-CENP-A interactions. Collectively, these data suggest that the losses of immunofluorescence signals of the central-outer kinetochore proteins at the kinetochore caused by SGT1 siRNA defects, including ones reported previously [174], are explained by CENP-A mislocalization caused by SGT1 siRNA defects.
4.5 CENP-A ubiquitylation is indispensable to cell viability
Our group reported that CENP-A K124 ubiquitylation, mediated by the CUL4A-RBX1-COPS8 complex, is essential for CENP-A deposition at the centromere [35] (Figure 2, right; see also Section 4.2). On the other hand, Fachinetti et al. reported that CENP-A K124R mutants show no defects in centromere localization and cell viability [156]. However, there are substantive problems with their experiments that yielded these results. We reported our response describing potential issues with the results and their conclusions [117]. A major caveat is that they used a fusion protein much larger molecular size than CENP-A. In their RPE-1 CENP-A−/F knockout system, the enhanced yellow fluorescent protein (EYFP) is approximately 30 kDa, and endogenous CENP-A is about 16 kDa. Fachinetti et al. also used SNAP-tags, and they found that SNAP-CENP-A K124R showed no defects in centromere deposition. Because the SNAP-tag (20 kDa) is also a larger tag than CENP-A (approximately 16 kDa) and has 10 lysines, SNAP-CENP-A K124R, presumably, is ubiquitylated at a site different than K124. One possibility is that the tagging of a large protein may endogenously lead to ubiquitylation at an amino acid other than K124 in the CENP-A K124R mutant protein, and this ubiquitylation at another site could suppress the mutant phenotype as a compensatory mechanism. Therefore, our group hypothesized that the presence of a large fusion protein promotes ubiquitylation at a different lysine in the CENP-A K124R mutant protein.
Indeed, our group found that EYFP tagging induces additional ubiquitylation of EYFP-CENP-A K124R, which allows the mutant protein to bind to HJURP [116]. Our immunoprecipitation mass spectrometry analysis showed that lysine 306 (K306) in the EYFP-CENP-A K124R mutant is ubiquitylated in vivo. This site corresponds to lysine 56 (K56) in CENP-A. These data suggest that once EYFP is tagged to a K124R mutant, another ubiquitylation occurs at a different site than K124 as endogenous compensatory machinery. Using a previously developed conditional CENP-A knockout system and our CENP-A K124R knockin mutant created by the CRISPR-Cas9 system, we show that the small size Flag-tagged or untagged CENP-A K124R mutant is lethal. This lethality is rescued by monoubiquitin fusion, indicating that CENP-A ubiquitylation is essential for viability. Therefore, our group suggests a caveat in the use of GFP/EYFP as a tool to analyze the function of a protein, and our data still support that the CENP-A ubiquitylation is indispensable to cell viability.
4.6 Hypothetical regulation of human CENP-A through sumoylation
In budding yeast, CENP-ACse4 is sumoylated on its N-terminal tail by Siz1/Siz2 SUMO E3 ligases [22] (previous chapter, Figure 1a and b) (see also previous chapter, Section 2.4.1). Cse4 is poly-sumoylated at K65 in its N-terminal domain, which recruits the yeast SUMO-targeted ubiquitin ligase (STUbl) Slx5, leading to the polyubiquitination of poly-sumoylated Cse4 and its subsequent degradation [21]. Cse4 K215/216 sumoylation in C-terminus also controls its interaction with the histone chaperones Scm3 and CAF-1, facilitating the deposition of overexpressed Cse4 into CEN and non-CEN regions, respectively [175] (previous chapter, Figure 1) (see also previous chapter, Section 2.4.2).
In humans, depletion of the human Slx5 homolog ring finger protein 4 (RNF4) contributes to SUMOylation-dependent degradation of the CCAN protein CENP-I, while SENP6 stabilizes CENP-I by antagonizing RNF4 [176]. SENP6 is a desumoylation enzyme as well as a member of a large family of Sentrin-specific protease enzymes (SENP1–7) [138, 177]. In budding yeast, two SUMO proteases are known, ubiquitin-like protease 1 and 2 (Ulp1 and 2); in mammalian cells, these have diverged into the SENP family. SENP1–5 is evolutionarily conserved to Ulp1, while the more divergent SENP6 and SENP7 belong to the Ulp2 group. Depletion of SENP6 in HeLa cells leads to the loss of the CENP-H/I/K complex from the centromeres, but not an apparent reduction in centromeric CENP-A/B/C levels recognized by CREST sera [176].
Liebelt et al. identified a protein group de-modification by SENP6, including the constitutive centromere-associated network (CCAN), the CENP-A loading factors Mis18BP1 and Mis18A, and DNA damage response factors [178]. SENP6-deficient cells are severely compromised for proliferation, accumulate in the G2/M phases, and frequently form micronuclei. Centromeric assembly of CENP-T, CENP-W, and CENP-A is impaired in the absence of SENP6. However, the increase of SUMO chains is not required for ubiquitin-dependent proteasomal degradation of the CCAN subunits. Therefore, their results indicated that SUMO polymers can act in a proteolysis-independent manner and consequently, have a more diverse signaling function than previously expected. On the other hand, Mitra et al. identified the SUMO-protease SENP6 as a key factor, not only controlling CENP-A stability but virtually the entire centromere and kinetochore using a genetic screen coupled to pulse-chase labeling [179]. Loss of SENP6 results in hyper-sumoylation of CENP-C and CENP-I, but not CENP-A itself. SENP6 activity is required throughout the cell cycle, suggesting that a dynamic SUMO cycle underlies continuous surveillance of the centromere complex that in turn ensures stable transmission of CENP-A chromatin. Mitra et al. and other groups did not detect sumoylation of CENP-A, suggesting that CENP-A is not a direct substrate of SENP6 [138, 179]. However, the effect of SENP6 depletion on CENP-A stability is much greater than observed on depletion of CENP-C or -B alone [179]. This result suggests that there may be other components required for the SENP6-mediated stabilization of centromeric chromatin [138].
5. E3 ligases for plant CENP-A (CENH3) its function
5.1 Overview of plant CENP-A (CENH3)
Studies of E3 ligases at plant centromeres-kinetochores are not as advanced as those in model animal species. The structure and organization of plant centromeric DNA have been described, and satellite repeats associated with centromeres have been reported in many plant species [76]. Plant centromeres also have mega-base-sized arrays of tandem repetitive DNA sequences, as in centromeres of humans and other mammals, and transposable elements are abundant in centromeric and paracentromeric regions [76, 180]. In early studies, Jiang et al. suggest that the retention of active transcriptional machinery within the long terminal repeat may promote demarcation of an active centromere [76]. A Ty3/gypsy class of centromere-specific retrotransposons, the centromeric retrotransposon (CR) family, was discovered in the grass species. Highly conserved motifs were found in the long terminal repeat of the CR elements from rice, maize, and barley [181]. The CR elements are highly enriched in chromatin domains associated with CENH3/CENP-A, the centromere-specific histone H3 variant. CR elements as well as their flanking centromeric satellite DNA are actively transcribed in maize. These data suggest that the deposition of centromeric histones might be a transcription-coupled event. The importance of centromeric transcription and centromeric long noncoding RNA (cenRNA) for centromere integrity has been suggested in various species, including plants [77, 78, 79] (see also Sections 3 and 4). Moreover, in maize, CENP-C binding to centromeric DNA is associated with small RNA [182], whereas in humans CENP-A loading is linked to lncRNAs [80]. It is not yet known whether the same transcript can recruit and stabilize both CENP-A and CENP-C at centromeric chromatin [77].
Plant CENH3/CENP-A and other centromere-kinetochore proteins have been reported showing high conservation among species. On the other hand, DNA sequences of plant centromeres, of which loci are determined epigenetically by centromeric histone 3 (CENH3), have revealed high structural diversity, ranging from the canonical monocentric form seen in vertebrates, to polycentric and holocentric forms [183, 184]. Plant centromeres can change position over evolutionary time or upon genomic stress, such as in McClintock’s genome shock [185] or physically damaged or broken chromosomes [183]. Jiang et al. suggested that the centromeric state is reinforced and maintained by the tension applied during spindle attachment [76]. The chromatin damaged by such mechano-force could then be marked for repair by the replication-independent mechanism similar to the one originally incorporated in CENH3. Indeed, human centromere-kinetochore proteins, including CENP-A, are involved in DNA damage/repair [186], and the incorporation of newly synthesized CENP-A occurs “right after mitosis” (i.e., telophase/early G1) [94, 95]. However, the model of CenH3 (CENP-A) incorporation upon mechano-force-induced DNA damage/repair is not yet experimentally demonstrated, and its precise mechanism needs to be elucidated. Meanwhile, there is evidence of divergent evolution originating in CenH3 in plants [187, 188] and Drosophila [189]. The CenH3 (CENP-A) has apparently undergone both convergent and divergent evolution [7]. Nagaki et el. and others described that the centromere DNA repeats with which CENH3-containing nucleosome interacts are also highly diverged, proposing an “arms race” hypothesis where centromere DNA repeats are changing and expanding to increase their segregation properties, while CENH3 is changing to curb this process and keep segregation frequencies equal to avoid fixing traits [180, 184, 189, 190].
Plant studies of dicentric centromeres and neocentromeres have been described along with those of other eukaryotes [180, 183]. The active state of one of the two centromeres on the wheat dicentric chromosome can be epigenetically silenced [180], as in the human dicentric chromosome [191]. Neocentromeres have been described extensively in human and fruit fly chromosomes as well as in some plant species, such as barley, maize, and rice [114, 184, 192]. In D. melanogaster, Palladino et al. showed that multiple genomic locations can acquire centromere activity, using a LacO/LacI ectopic centromeric chromatin assembly system. In addition, they demonstrated that these de novo centromeres can be transmitted and maintained epigenetically in mitotic tissues [114]. Although studies of human neocentromeres have indicated that they are generated at new positions in a single step; the barley neocentromere appears to have shifted several times along the chromosomal arm region during the deletion steps to finally reach the observed position [180]. The emergence of new centromeres was also observed in hybrid conditions [183, 184], and Wang et al. described the proposed model for hybrids between maize and oat [193]. The “centromere repositioning” then generates neocentromeres; the establishment of a new centromere does not require specific DNA composition in the target loci [76, 194]. Most new centromeres have no satellite DNA [195]. However, most mature centromeres are overwhelmingly composed of repetitive DNA, especially satellite DNA [76, 194]. One hypothesis to explain this apparent contradiction was described by Oliveira et al. as “satellite DNA invasion mechanism”—a new satellite repeat or one already present in other centromeres may invade and occupy the CenH3 domain of the new centromere [184]. The satellite DNA invasion mechanism is still elusive, and the retrotransposons would be the main source for the origin of new repeats [184, 196].
Plant studies of minichromosomes and artificial chromosomes also have been reported, as in other eukaryotes [180, 183]. The main issues of these studies are what are the size and factors required for the maintenance and stability of such special chromosomes during cell division. Harrington et al. constructed human artificial minichromosomes [197], and Ananiev et al. artificially generated minichromosomes in maize by introducing the DNA molecule containing native centromere segment, ori, and telomere repeats [198]. These studies suggested that repetitive DNA may play an important but unknown role in centromere function. The repetitive centromeric DNA may be still important, although it is not essential for centromeric function, since plant centromeric DNA does not generate functional centromeres when reintroduced into plant cells [199] and new centromeres are functional even if located in loci with non-centromeric DNA [161].
In terms of the plant CENH3 recruitment mechanism to centromeres, most CENP-A is loaded in G2 by a replication-independent mechanism in Arabidopsis thaliana [200]. However, in plants as in other species, the timing of deposition of newly synthesized CENP-A within the cell cycle may be variable—not only among different plant species but also different developmental stages within the same species. Le Goff et al. reported that the H3 histone chaperone NASPSIM3 escorts CENH3 in Arabidopsis [19]. They showed that the Arabidopsis ortholog of the mammalian nuclear autoantigenic sperm protein (NASP) and S. pombe histone chaperone Sim3 is a soluble nuclear protein that interacts with CENH3 and influences its abundance at the centromeres [19]. NASPSIM3 is co-expressed with Arabidopsis CENH3 in dividing cells and binds directly to both the N-terminal tail and the C-terminal histone fold domain of non-nucleosomal CENH3. Reduced NASPSIM3 expression by NASPSIM3 knockdown impairs CenH3 deposition. Thus, they identified NASPSIM3 as a CenH3 histone chaperone as demonstrated in fission yeast (see also Section 2.1).
5.2 Engineered degradation of EYFP-tagged CENH3 in plants
Currently, an endogenous E3 ligase for plant CENP-A (CENH3) is not yet identified. Sorge et al. developed a synthetic biology approach to degrade plant CENP-A using E3-ligase adapter protein SPOP (Speckle-type POZ adapter protein) with a specific anti-GFP nanobody (VHHGFP4) [201] (Table 1). To determine the function of proteins, CRISPR/Cas9-based methods and antisense/RNAi strategies are commonly used to remove the selected protein from all organs in a cell- and tissue-specific manner. However, CRISPR/Cas9 and antisense/RNAi strategies are still error-prone and can show off-target effects [202]. Classical genetic strategies to knock out/down protein function in plants still have problems, such as the time-consuming process of generating homozygous transgenic lines or the risk of lethal phenotypes at early developmental stages.
Sorge et al. attempted to solve these problems by utilizing the synthetic E3 ligase activity in protein ubiquitylation and degradation pathway. They successfully recruited the 26S proteasome pathway to directly degrade CENP-A of A. thaliana via replacement of the interaction domain of the E3 ligase adaptor protein SPOP (Speckle-type POZ adapter protein) with a specific anti-GFP nanobody (VHHGFP4). They proved that the target protein CENH3 of A. thaliana fused to EYFP was subjected to nanobody-guided proteasomal degradation in planta. Thus, their results show the potential of the modified E3-ligase adapter protein VHHGFP4-SPOP to induce nucleus-specific protein degradation in plants. However, further studies are required to identify endogenous E3 ligase for plant CENP-A (CENH3) and determine the function of the plant CENP-A (CENH3) proteolysis or deposition at centromeres.
6. Conclusions
Each species reviewed in our articles, including the previous chapter has advantages and disadvantages for research. For example, the centromere sequence size of the budding yeast is small and the sequences can be easily mutated to identify the important functional regions [203]. Techniques such as ChIP are also possible, which cannot be easily performed on highly repetitive centromeres in other organisms. Moreover, the centromere can be shifted to other genomic regions, allowing the construction of artificial chromosomes and plasmids as well as tools, such as conditional centromeres. Fission yeast and fruit fly models have progressed more than others in studies of heterochromatin regulation and gene silencing. Plant models have advanced more in evolutionary studies of centromeric DNA structures, including CR family comparisons among different plant species.
On the other hand, in fission yeast and plant species, the E3 ligase of CENP-A (CenH3) and its specific regulation and/or function are not yet identified. The E3 ligase of CENP-A is unknown in multiple species (e.g., Caenorhabditis elegans, Xenopus laevis, zebrafish Danio rerio, chicken Gallus domesticus DT40 cells, Mus musculus, etc.) or this research is sparse in these species compared with others. At present, the most common species studied and reported in the past for E3 ligase of CenH3 (Cse4) is budding yeast. However, in other species, much is not understood, particularly about control of the balance between E3 ligase and deubiquitylase and the balance among SUMO E3 ligase, the desumoylation enzyme, SUMO proteases (e.g., SENP6). Future research into the E3 ligases of CENP-A will elucidate the regulation and mechanisms of these subtle balances in each species and human diseases.
Studying the mechanisms of formation and maintenance of neocentromeres will deepen our understanding of the centromere-kinetochore formation and promote the building and establishment of artificial chromosomes. Such studies will lead to the construction of artificial cells and tissues that can be controlled by DNA levels through chromosome dynamics. As a result, the function of E3 ligase can be artificially adjusted, which will increase the effectiveness of future gene therapies. Minichromosomes generated to date suggest that the repetitive centromeric DNA may be still important, although perhaps, it is not essential for centromeric function. In addition, it is unclear whether there is causality or feedback between cenRNA transcription and overall transcriptional change after chromosome missegregation and CIN. As of now, we have little understanding of the effects of these cenRNAs on the E3 ligase of CENP-A, including how these transcriptional changes and regulation are related to the function of E3 ligase.
Although our group showed that ubiquitylation occurs at a different site than CENP-A K124 as endogenous compensatory machinery, the compensatory machinery of post-translational modifications in endogenous conditions is poorly understood. This machinery can be incorporated in a process of disease progress or development. For example, suppose a post-translational modification is required for host cancer cell development but its activity can be blocked by cancer drugs. However, another site’s post-translational modification could compensate for that change, so that host cancer cells can survive, proliferate, and eventually metastasize. For cell proliferation and differentiation in general, such compensatory machinery could be a versatile backup system. However, such backup systems may not have been detected experimentally due to our limited technology or brief experimental periods. Thus, many E3 ligases may work in similar signal pathways (see also the previous chapter, Conclusion), or the function of a post-translational modification in one site may be compensated for or complemented by another site, but it is currently unknown how likely such complementary machineries would be. Research to predict such compensatory systems and resilience could be expected as future directions to study the spatiotemporal regulation of E3 ligase of CENP-A.
Ultimately, studies of E3 ligase in CENP-A in higher mammals or humans are essential for translational research and informing future therapy. Overexpression and mislocalization of human CENP-A are presumably features of cancer development, however, the detailed mechanisms for cancer development and possible therapies still remain unclear. In addition to cancer, translational studies of CENP-A and its E3 ligase could be beneficial for CREST autoimmune diseases and other diseases. Centromere proteins, including CENP-A, have been identified as antigens from CREST patients [204, 205], but the mechanism that causes CREST syndrome and how CENP-A and other centromere-kinetochore proteins are involved is unknown. Observations of neocentromeres were also reported in patients with other developmental diseases [206], but research has been limited, in part because of the relatively smaller number of patients.
Defects in ubiquitin E3 ligases promote the pathogenesis of several human diseases, including cancer, and CRL4 [207], a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in cancers [208]. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. In humans, proteolysis activity of CRL4 ubiquitin ligase targeting CENP-A has not been observed so far, and other E3 ligases that function in CENP-A proteolysis are unidentified (Figure 2d). It is also important to determine if ubiquitylation or sumoylation-related enzymes, including E3 ligases, can be druggable targets.
Tumors develop in complex tissue microenvironments, where they depend on for sustained growth, invasion, and metastasis [209]. We could be at a turning point to fill the gap between the detailed intracellular mechanisms of CENP-A function studied in the past and its mechanism in complex tissue microenvironments. Thus, cell type and/or tissue-specific CENP-A function involved in different types of cancer in different organs is a likely focus for future research. There are many unknowns about whether the function of E3 ligase of CENP-A represents a cell or tissue-specific difference, or whether the cell or tissue completely replaces E3 ligase itself. The utilization and application of organoid, spheroid, and coculture systems may reduce the effort, time, and cost that is required to answer these questions and ultimately yield better therapies.
Acknowledgments
We thank past and current researchers at Model Animal Research Center, School of Medicine, Nanjing University, Greehey Children’s Cancer Research Institute at UT Health Science Center San Antonio, the Research Institute at Nationwide Children’s Hospital, and St. Jude Children’s Research Hospital for their helpful discussions. Y.N. was supported by Jiangsu Province “Double-First-Class” Construction Fund, Jiangsu Province Natural Science Fund (BK20191252), Jiangsu Province 16th Six Big Talent Peaks Fund (TD-SWYY-001), Jiangsu Province “Foreign Expert Hundred Talents Program” Fund (BX2019082), and National Natural Science Foundation in China (31970665). KK was supported by the National Science Foundation under Grant No.1949653 (KK) and a Mays Cancer Center Pilot Award CCSG P30 CA054174.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"CENP-A, Cse4, Cnp1, CID, E3 ligase, centromere, kinetochore, ubiquitylation, sumoylation, epigenetics, Psh1, Siz1 and Siz2, Slx5 and Slx8, CUL3/RDX, SCF, APC, CUL4A/RBX1/COPS8, DAXX (fruit fly DLP), SGT1-HSP90, Scm3, CAF-1 complex, CAL1, HJURP, Mis18 (human Mis18α and Mis18β) and Mis16 (human RbAp46 and RbAp48)",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80730.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80730.xml",downloadPdfUrl:"/chapter/pdf-download/80730",previewPdfUrl:"/chapter/pdf-preview/80730",totalDownloads:61,totalViews:0,totalCrossrefCites:0,dateSubmitted:null,dateReviewed:"January 4th 2022",datePrePublished:"March 6th 2022",datePublished:"June 15th 2022",dateFinished:"March 5th 2022",readingETA:"0",abstract:"Centromeric CENP-A, a variant of histone H3, plays a central role in proper chromosome segregation and its function is highly conserved among different species. In most species with regional centromeres, an active centromere relies not on defined DNA sequences, but on the presence of CENP-A proteins in centromeric nucleosomes. CENP-A is proposed to be the non-DNA indicator (epigenetic mark) that defines proper centromere assembly and function. Recently, many post-translational modifications (PTMs) of CENP-A and their functions have been reported. They revealed the importance of the functions of CENP-A PTMs in CENP-A deposition at centromeres, proteolysis/protein stability, and recruitment of other centromere-kinetochore proteins. Ubiquitylation and sumoylation by E3 ligases regulate multiple functions, including proteolysis and signaling, and play important roles in the cell cycle and mitotic control. Recently, the function of E3 ligase that ubiquitylates/sumoylates and controls CENP-A protein has emerged as an important regulatory paradigm in different species. Many have reported the importance of CENP-A ubiquitylation and sumoylation in CENP-A deposition at centromeres and for protein stability, which is regulated by specific E3 ligases. Therefore, here we summarize what is known about the E3 ligases for CENP-A ubiquitylation and sumoylation and their biological functions and significance in different species.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80730",risUrl:"/chapter/ris/80730",signatures:"Yohei Niikura and Katsumi Kitagawa",book:{id:"10841",type:"book",title:"Hydrolases",subtitle:null,fullTitle:"Hydrolases",slug:"hydrolases",publishedDate:"June 15th 2022",bookSignature:"Sajjad Haider, Adnan Haider and Angel Catalá",coverURL:"https://cdn.intechopen.com/books/images_new/10841.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-80355-163-0",printIsbn:"978-1-80355-162-3",pdfIsbn:"978-1-80355-164-7",isAvailableForWebshopOrdering:!0,editors:[{id:"110708",title:"Dr.",name:"Sajjad",middleName:null,surname:"Haider",slug:"sajjad-haider",fullName:"Sajjad Haider"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"427825",title:"Associate Prof.",name:"Katsumi",middleName:null,surname:"Kitagawa",fullName:"Katsumi Kitagawa",slug:"katsumi-kitagawa",email:"kitagawak@uthscsa.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"428604",title:"Dr.",name:"Yohei",middleName:null,surname:"Niikura",fullName:"Yohei Niikura",slug:"yohei-niikura",email:"niikura@nicemice.cn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Nanjing University",institutionURL:null,country:{name:"China"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. E3 ligase for fission yeast (Schizosaccharomyces pombe) CENP-ACnp1 and its function",level:"1"},{id:"sec_2_2",title:"2.1 Overview of CENP-ACnp1",level:"2"},{id:"sec_3_2",title:"2.2 Dos1/2-Cdc20 complex",level:"2"},{id:"sec_4_2",title:"2.3 Assembly of Cnp1 at non-centromeric chromatin",level:"2"},{id:"sec_5_2",title:"2.4 Heterochromatin and RNAi regulate centromeres by protecting Cnp1 from ubiquitin-mediated degradation",level:"2"},{id:"sec_7",title:"3. E3 ligase for fruit fly (Drosophila melanogaster) CENP-ACID and its function",level:"1"},{id:"sec_7_2",title:"3.1 Overview of CENP-ACID",level:"2"},{id:"sec_8_2",title:"3.2 CUL3/RDX E3 Ligase",level:"2"},{id:"sec_9_2",title:"3.3 The E3-ligases SCFPpa and APC/CCdh1 co-operate to regulate CID expression across the cell cycle",level:"2"},{id:"sec_10_2",title:"3.4 Phosphorylation of Drosophila CID on serine 20 regulates protein turnover and centromere-specific loading",level:"2"},{id:"sec_12",title:"4. E3 ligase for human CENP-A its function",level:"1"},{id:"sec_12_2",title:"4.1 Overview of human CENP-A",level:"2"},{id:"sec_13_2",title:"4.2 CENP-A K124 ubiquitylation is required for CENP-A deposition at the centromere",level:"2"},{id:"sec_14_2",title:"4.3 CENP-A ubiquitylation is inherited through dimerization between cell divisions",level:"2"},{id:"sec_15_2",title:"4.4 SGT1-HSP90 complex is required for CENP-A loading at centromeres",level:"2"},{id:"sec_16_2",title:"4.5 CENP-A ubiquitylation is indispensable to cell viability",level:"2"},{id:"sec_17_2",title:"4.6 Hypothetical regulation of human CENP-A through sumoylation",level:"2"},{id:"sec_19",title:"5. E3 ligases for plant CENP-A (CENH3) its function",level:"1"},{id:"sec_19_2",title:"5.1 Overview of plant CENP-A (CENH3)",level:"2"},{id:"sec_20_2",title:"5.2 Engineered degradation of EYFP-tagged CENH3 in plants",level:"2"},{id:"sec_22",title:"6. Conclusions",level:"1"},{id:"sec_23",title:"Acknowledgments",level:"1"},{id:"sec_26",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Allshire RC, Karpen GH. Epigenetic regulation of centromeric chromatin: Old dogs, new tricks? Nature Reviews. Genetics. 2008;9(12):923-937. DOI: 10.1038/nrg2466'},{id:"B2",body:'Black BE, Foltz DR, Chakravarthy S, Luger K, Woods VL Jr, Cleveland DW. Structural determinants for generating centromeric chromatin. Nature. 2004;430(6999):578-582. DOI: 10.1038/nature02766'},{id:"B3",body:'Sekulic N, Bassett EA, Rogers DJ, Black BE. The structure of (CENP-A-H4)(2) reveals physical features that mark centromeres. Nature. 2010;467(7313):347-351. DOI: 10.1038/nature09323'},{id:"B4",body:'Tachiwana H et al. Crystal structure of the human centromeric nucleosome containing CENP-A. Nature. 2011;476(7359):232-235. DOI: 10.1038/nature10258'},{id:"B5",body:'Black BE, Cleveland DW. Epigenetic centromere propagation and the nature of CENP-a nucleosomes (in eng). Cell. 2011;144(4):471-479. DOI: 10.1016/j.cell.2011.02.002'},{id:"B6",body:'Liu ST, Rattner JB, Jablonski SA, Yen TJ. Mapping the assembly pathways that specify formation of the trilaminar kinetochore plates in human cells. The Journal of Cell Biology. 2006;175(1):41-53. DOI: 10.1083/jcb.200606020'},{id:"B7",body:'Ekwall K. Epigenetic control of centromere behavior. Annual Review of Genetics. 2007;41:63-81. DOI: 10.1146/annurev.genet.41.110306.130127'},{id:"B8",body:'Aravamudhan P, Felzer-Kim I, Joglekar AP. The budding yeast point centromere associates with two Cse4 molecules during mitosis. Current Biology. 2013;23(9):770-774. DOI: 10.1016/j.cub.2013.03.042'},{id:"B9",body:'Bodor DL et al. The quantitative architecture of centromeric chromatin. eLife. 2014;3:e02137. DOI: 10.7554/eLife.02137'},{id:"B10",body:'Coffman VC, Wu P, Parthun MR, Wu JQ. CENP-A exceeds microtubule attachment sites in centromere clusters of both budding and fission yeast. The Journal of Cell Biology. 2011;195(4):563-572. DOI: 10.1083/jcb.201106078'},{id:"B11",body:'Lawrimore J, Bloom KS, Salmon ED. Point centromeres contain more than a single centromere-specific Cse4 (CENP-A) nucleosome. The Journal of Cell Biology. 2011;195(4):573-582. DOI: 10.1083/jcb.201106036'},{id:"B12",body:'Black BE et al. Centromere identity maintained by nucleosomes assembled with histone H3 containing the CENP-A targeting domain. Molecular Cell. 2007;25(2):309-322. DOI: 10.1016/j.molcel.2006.12.018'},{id:"B13",body:'Carroll CW, Milks KJ, Straight AF. Dual recognition of CENP-A nucleosomes is required for centromere assembly. The Journal of Cell Biology. 2010;189(7):1143-1155. DOI: 10.1083/jcb.201001013'},{id:"B14",body:'Guse A, Carroll CW, Moree B, Fuller CJ, Straight AF. In vitro centromere and kinetochore assembly on defined chromatin templates. Nature. 2011;477(7364):354-358. DOI: 10.1038/nature10379'},{id:"B15",body:'Carroll CW, Silva MC, Godek KM, Jansen LE, Straight AF. Centromere assembly requires the direct recognition of CENP-A nucleosomes by CENP-N. Nature Cell Biology. 2009;11(7):896-902. DOI: 10.1038/ncb1899'},{id:"B16",body:'Au WC, Dawson AR, Rawson DW, Taylor SB, Baker RE, Basrai MA. A novel role of the N terminus of budding yeast histone H3 variant Cse4 in ubiquitin-mediated proteolysis. Genetics. 2013;194(2):513-518. DOI: 10.1534/genetics.113.149898'},{id:"B17",body:'Folco HD et al. The CENP-A N-tail confers epigenetic stability to centromeres via the CENP-T branch of the CCAN in fission yeast. Current Biology. 2015;25(3):348-356. DOI: 10.1016/j.cub.2014.11.060'},{id:"B18",body:'Gonzalez M, He H, Dong Q, Sun S, Li F. Ectopic centromere nucleation by CENP--a in fission yeast. Genetics. 2014;198(4):1433-1446. DOI: 10.1534/genetics.114.171173'},{id:"B19",body:'Le Goff S et al. The H3 histone chaperone NASP(SIM3) escorts CenH3 in Arabidopsis. The Plant Journal. 2020;101(1):71-86. DOI: 10.1111/tpj.14518'},{id:"B20",body:'Logsdon GA et al. Both tails and the centromere targeting domain of CENP-A are required for centromere establishment. The Journal of Cell Biology. 2015;208(5):521-531. DOI: 10.1083/jcb.201412011'},{id:"B21",body:'Ohkuni K et al. N-terminal sumoylation of centromeric histone H3 variant Cse4 regulates its proteolysis to prevent mislocalization to non-centromeric chromatin. G3 (Bethesda). 2018;8(4):1215-1223. DOI: 10.1534/g3.117.300419'},{id:"B22",body:'Ohkuni K et al. SUMO-targeted ubiquitin ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin. Molecular Biology of the Cell. 2016;27(9):1500-1510. DOI: 10.1091/mbc.E15-12-0827'},{id:"B23",body:'Ranjitkar P, Press MO, Yi X, Baker R, MacCoss MJ, Biggins S. An E3 ubiquitin ligase prevents ectopic localization of the centromeric histone H3 variant via the centromere targeting domain. Molecular Cell. 2010;40(3):455-464. DOI: 10.1016/j.molcel.2010.09.025'},{id:"B24",body:'Tan HL et al. Prolyl isomerization of the CENP-A N-terminus regulates centromeric integrity in fission yeast. Nucleic Acids Research. 2018;46(3):1167-1179. DOI: 10.1093/nar/gkx1180'},{id:"B25",body:'Tan HL, Zeng YB, Chen ES. N-terminus does not govern protein turnover of Schizosaccharomyces pombe CENP-A. International Journal of Molecular Sciences. 2020;21(17):1-13. DOI: 10.3390/ijms21176175'},{id:"B26",body:'Yang J et al. Heterochromatin and RNAi regulate centromeres by protecting CENP-A from ubiquitin-mediated degradation. PLoS Genetics. 2018;14(8):e1007572. DOI: 10.1371/journal.pgen.1007572'},{id:"B27",body:'Zhou Z et al. Structural basis for recognition of centromere histone variant CenH3 by the chaperone Scm3. Nature. 2011;472(7342):234-237. DOI: 10.1038/nature09854'},{id:"B28",body:'Bernad R, Sanchez P, Losada A. Epigenetic specification of centromeres by CENP-A. Experimental Cell Research. 2009;315(19):3233-3241. DOI: 10.1016/j.yexcr.2009.07.023'},{id:"B29",body:'Sanchez-Pulido L, Pidoux AL, Ponting CP, Allshire RC. Common ancestry of the CENP-A chaperones Scm3 and HJURP. Cell. 2009;137(7):1173-1174. DOI: 10.1016/j.cell.2009.06.010'},{id:"B30",body:'Bade D, Pauleau AL, Wendler A, Erhardt S. The E3 ligase CUL3/RDX controls centromere maintenance by ubiquitylating and stabilizing CENP-A in a CAL1-dependent manner. Developmental Cell. 2014;28(5):508-519. DOI: 10.1016/j.devcel.2014.01.031'},{id:"B31",body:'Merlet J, Burger J, Gomes JE, Pintard L. Regulation of cullin-RING E3 ubiquitin-ligases by neddylation and dimerization. Cellular and Molecular Life Sciences. 2009;66(11-12):1924-1938. DOI: 10.1007/s00018-009-8712-7'},{id:"B32",body:'Moreno-Moreno O, Torras-Llort M, Azorin F. The E3-ligases SCFPpa and APC/CCdh1 co-operate to regulate CENP-ACID expression across the cell cycle. Nucleic Acids Research. 2019;47(7):3395-3406. DOI: 10.1093/nar/gkz060'},{id:"B33",body:'Huang A et al. Phosphorylation of Drosophila CENP-A on serine 20 regulates protein turn-over and centromere-specific loading. Nucleic Acids Research. 2019;47(20):10754-10770. DOI: 10.1093/nar/gkz809'},{id:"B34",body:'Lacoste N et al. Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX. Molecular Cell. 2014;53(4):631-644. DOI: 10.1016/j.molcel.2014.01.018'},{id:"B35",body:'Niikura Y, Kitagawa R, Ogi H, Abdulle R, Pagala V, Kitagawa K. CENP-A K124 ubiquitylation is required for CENP-A deposition at the centromere. Developmental Cell. 2015;32(5):589-603. DOI: 10.1016/j.devcel.2015.01.024'},{id:"B36",body:'Ahn J et al. The cullin-RING E3 ubiquitin ligase CRL4-DCAF1 complex dimerizes via a short helical region in DCAF1. Biochemistry. 2011;50(8):1359-1367. DOI: 10.1021/bi101749s'},{id:"B37",body:'Chew EH, Poobalasingam T, Hawkey CJ, Hagen T. Characterization of cullin-based E3 ubiquitin ligases in intact mammalian cells--evidence for cullin dimerization. Cellular Signalling. 2007;19(5):1071-1080. DOI: 10.1016/j.cellsig.2006.12.002'},{id:"B38",body:'Bui M et al. Cell-cycle-dependent structural transitions in the human CENP-A nucleosome in vivo. Cell. 2012;150(2):317-326. DOI: 10.1016/j.cell.2012.05.035'},{id:"B39",body:'Bui M et al. Internal modifications in the CENP-A nucleosome modulate centromeric dynamics. Epigenetics & Chromatin. 2017;10:17. DOI: 10.1186/s13072-017-0124-6'},{id:"B40",body:'Niikura Y, Kitagawa R, Kitagawa K. The inheritance of centromere identity. Molecular & Cellular Oncology. 2016;3(4):e1188226. DOI: 10.1080/23723556.2016.1188226'},{id:"B41",body:'Barnhart MC et al. HJURP is a CENP-A chromatin assembly factor sufficient to form a functional de novo kinetochore. The Journal of Cell Biology. 2011;194(2):229-243. DOI: 10.1083/jcb.201012017'},{id:"B42",body:'Dunleavy EM et al. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell. 2009;137(3):485-497. DOI: 10.1016/j.cell.2009.02.040'},{id:"B43",body:'Foltz DR et al. Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP (in eng). Cell. 2009;137(3):472-484. DOI: 10.1016/j.cell.2009.02.039'},{id:"B44",body:'Zasadzinska E, Foltz DR. Orchestrating the specific assembly of centromeric nucleosomes. Progress in Molecular and Subcellular Biology. 2017;56:165-192. DOI: 10.1007/978-3-319-58592-5_7'},{id:"B45",body:'Srivastava S, Foltz DR. Posttranslational modifications of CENP-A: Marks of distinction. Chromosoma. 2018;127(3):279-290. DOI: 10.1007/s00412-018-0665-x'},{id:"B46",body:'Partridge JF. Centromeric chromatin in fission yeast. Frontiers in Bioscience. 2008;13:3896-3905. DOI: 10.2741/2977'},{id:"B47",body:'Creamer KM, Partridge JF. RITS-connecting transcription, RNA interference, and heterochromatin assembly in fission yeast. Wiley Interdisciplinary Reviews: RNA. 2011;2(5):632-646. DOI: 10.1002/wrna.80'},{id:"B48",body:'Pidoux AL et al. Fission yeast Scm3: A CENP-A receptor required for integrity of subkinetochore chromatin. Molecular Cell. 2009;33(3):299-311. DOI: 10.1016/j.molcel.2009.01.019'},{id:"B49",body:'Williams JS, Hayashi T, Yanagida M, Russell P. Fission yeast Scm3 mediates stable assembly of Cnp1/CENP-A into centromeric chromatin. Molecular Cell. 2009;33(3):287-298. DOI: 10.1016/j.molcel.2009.01.017'},{id:"B50",body:'Dunleavy EM et al. A NASP (N1/N2)-related protein, Sim3, binds CENP-A and is required for its deposition at fission yeast centromeres. Molecular Cell. 2007;28(6):1029-1044. DOI: 10.1016/j.molcel.2007.10.010'},{id:"B51",body:'Liu H et al. Structural insights into yeast histone chaperone Hif1: A scaffold protein recruiting protein complexes to core histones. The Biochemical Journal. 2014;462(3):465-473. DOI: 10.1042/BJ20131640'},{id:"B52",body:'Tanae K, Horiuchi T, Yamakawa T, Matsuo Y, Kawamukai M. Sim3 shares some common roles with the histone chaperone Asf1 in fission yeast. FEBS Letters. 2012;586(23):4190-4196. DOI: 10.1016/j.febslet.2012.10.020'},{id:"B53",body:'Tanae K, Horiuchi T, Matsuo Y, Katayama S, Kawamukai M. Histone chaperone Asf1 plays an essential role in maintaining genomic stability in fission yeast. PLoS One. 2012;7(1):e30472. DOI: 10.1371/journal.pone.0030472'},{id:"B54",body:'Fujita Y et al. Priming of centromere for CENP-A recruitment by human hMis18alpha, hMis18beta, and M18BP1. Developmental Cell. 2007;12(1):17-30. DOI: 10.1016/j.devcel.2006.11.002'},{id:"B55",body:'Hayashi T, Fujita Y, Iwasaki O, Adachi Y, Takahashi K, Yanagida M. Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres. Cell. 2004;118(6):715-729. DOI: 10.1016/j.cell.2004.09.002'},{id:"B56",body:'Loyola A, Almouzni G. Histone chaperones, a supporting role in the limelight. Biochimica et Biophysica Acta. 2004;1677(1-3):3-11. DOI: 10.1016/j.bbaexp.2003.09.012'},{id:"B57",body:'Shang WH et al. Chromosome engineering allows the efficient isolation of vertebrate neocentromeres. Developmental Cell. 2013;24(6):635-648. DOI: 10.1016/j.devcel.2013.02.009'},{id:"B58",body:'Boltengagen M et al. A novel role for the histone acetyltransferase Hat1 in the CENP-A/CID assembly pathway in Drosophila melanogaster. Nucleic Acids Research. 2016;44(5):2145-2159. DOI: 10.1093/nar/gkv1235'},{id:"B59",body:'Kim IS et al. Roles of Mis18alpha in epigenetic regulation of centromeric chromatin and CENP-A loading. Molecular Cell. 2012;46(3):260-273. DOI: 10.1016/j.molcel.2012.03.021'},{id:"B60",body:'Hayashi T, Ebe M, Nagao K, Kokubu A, Sajiki K, Yanagida M. Schizosaccharomyces pombe centromere protein Mis19 links Mis16 and Mis18 to recruit CENP-A through interacting with NMD factors and the SWI/SNF complex. Genes to Cells. 2014;19(7):541-554. DOI: 10.1111/gtc.12152'},{id:"B61",body:'Subramanian L, Toda NR, Rappsilber J, Allshire RC. Eic1 links Mis18 with the CCAN/Mis6/Ctf19 complex to promote CENP-A assembly. Open Biology. 2014;4:140043. DOI: 10.1098/rsob.140043'},{id:"B62",body:'Subramanian L et al. Centromere localization and function of Mis18 requires Yippee-like domain-mediated oligomerization. EMBO Reports. 2016;17(4):496-507. DOI: 10.15252/embr.201541520'},{id:"B63",body:'Ohkuni K, Abdulle R, Kitagawa K. Degradation of centromeric histone H3 variant Cse4 requires the Fpr3 peptidyl-prolyl Cis-Trans isomerase. Genetics. 2014;196(4):1041-1045. DOI: 10.1534/genetics.114.161224'},{id:"B64",body:'Pearson CG, Yeh E, Gardner M, Odde D, Salmon ED, Bloom K. Stable kinetochore-microtubule attachment constrains centromere positioning in metaphase. Current Biology. 2004;14(21):1962-1967. DOI: 10.1016/j.cub.2004.09.086'},{id:"B65",body:'Takayama Y, Sato H, Saitoh S, Ogiyama Y, Masuda F, Takahashi K. Biphasic incorporation of centromeric histone CENP-A in fission yeast. Molecular Biology of the Cell. 2008;19(2):682-690. DOI: 10.1091/mbc.e07-05-0504'},{id:"B66",body:'Gonzalez M, He H, Sun S, Li C, Li F. Cell cycle-dependent deposition of CENP-A requires the Dos1/2-Cdc20 complex. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(2):606-611. DOI: 10.1073/pnas.1214874110'},{id:"B67",body:'Li F, Martienssen R, Cande WZ. Coordination of DNA replication and histone modification by the Rik1-Dos2 complex. Nature. 2011;475(7355):244-248. DOI: 10.1038/nature10161'},{id:"B68",body:'Horn PJ, Bastie JN, Peterson CL. A Rik1-associated, cullin-dependent E3 ubiquitin ligase is essential for heterochromatin formation. Genes & Development. 2005;19(14):1705-1714. DOI: 10.1101/gad.1328005'},{id:"B69",body:'Hong EJ, Villen J, Gerace EL, Gygi SP, Moazed D. A cullin E3 ubiquitin ligase complex associates with Rik1 and the Clr4 histone H3-K9 methyltransferase and is required for RNAi-mediated heterochromatin formation. RNA Biology. 2005;2(3):106-111. DOI: 10.4161/rna.2.3.2131'},{id:"B70",body:'Hewawasam G et al. Psh1 is an E3 ubiquitin ligase that targets the centromeric histone variant Cse4. Molecular Cell. 2010;40(3):444-454. DOI: 10.1016/j.molcel.2010.10.014'},{id:"B71",body:'Hewawasam GS, Gerton JL. Cse4 gets a kiss-of-death from Psh1. Cell Cycle. 2011;10(4):566-567. DOI: 10.4161/cc.10.4.14770'},{id:"B72",body:'Castillo AG et al. Plasticity of fission yeast CENP-A chromatin driven by relative levels of histone H3 and H4. PLoS Genetics. 2007;3(7):e121. DOI: 10.1371/journal.pgen.0030121'},{id:"B73",body:'Au WC, Crisp MJ, DeLuca SZ, Rando OJ, Basrai MA. Altered dosage and mislocalization of histone H3 and Cse4p lead to chromosome loss in Saccharomyces cerevisiae. Genetics. 2008;179(1):263-275. DOI: 10.1534/genetics.108.088518'},{id:"B74",body:'Sullivan BA. Cell architecture and function/centromeres. In: Encyclopedia of Biological Chemistry II. 2nd ed. Elsevier Inc; 2013. pp. 500-502. DOI: 10.1016/B978-0-12-374984-0.00219-9'},{id:"B75",body:'Brown JD, O\'Neill RJ. The Evolution of Centromeric DNA Sequences. Wiley; 2014. DOI: 10.1002/9780470015902.a0020827.pub2. https://onlinelibrary.wiley.com/doi/10.1002/9780470015902.a0020827.pub2'},{id:"B76",body:'Jiang J, Birchler JA, Parrott WA, Dawe RK. A molecular view of plant centromeres. Trends in Plant Science. 2003;8(12):570-575. DOI: 10.1016/j.tplants.2003.10.011'},{id:"B77",body:'Arunkumar G, Melters DP. Centromeric transcription: A conserved swiss-army knife. Genes (Basel). 2020;11(8):1-22. DOI: 10.3390/genes11080911'},{id:"B78",body:'Leclerc S, Kitagawa K. The role of human centromeric RNA in chromosome stability. Frontiers in Molecular Biosciences. 2021;8:642732. DOI: 10.3389/fmolb.2021.642732'},{id:"B79",body:'Rosic S, Erhardt S. No longer a nuisance: Long non-coding RNAs join CENP-A in epigenetic centromere regulation. Cellular and Molecular Life Sciences. 2016;73(7):1387-1398. DOI: 10.1007/s00018-015-2124-7'},{id:"B80",body:'Quenet D, Dalal Y. A long non-coding RNA is required for targeting centromeric protein A to the human centromere. eLife. 2014;3:e03254. DOI: 10.7554/eLife.03254'},{id:"B81",body:'Elgin SC. Heterochromatin and gene regulation in Drosophila. Current Opinion in Genetics & Development. 1996;6(2):193-202. DOI: 10.1016/s0959-437x(96)80050-5'},{id:"B82",body:'Elgin SC, Reuter G. Position-effect variegation, heterochromatin formation, and gene silencing in Drosophila. Cold Spring Harbor Perspectives in Biology. 2013;5(8):a017780. DOI: 10.1101/cshperspect.a017780'},{id:"B83",body:'Walther M et al. Heterochromatin formation in Drosophila requires genome-wide histone deacetylation in cleavage chromatin before mid-blastula transition in early embryogenesis. Chromosoma. 2020;129(1):83-98. DOI: 10.1007/s00412-020-00732-x'},{id:"B84",body:'Riddle NC, Elgin SC. A role for RNAi in heterochromatin formation in Drosophila. Current Topics in Microbiology and Immunology. 2008;320:185-209. DOI: 10.1007/978-3-540-75157-1_9'},{id:"B85",body:'Gu T, Elgin SC. Maternal depletion of Piwi, a component of the RNAi system, impacts heterochromatin formation in Drosophila. PLoS Genetics. 2013;9(9):e1003780. DOI: 10.1371/journal.pgen.1003780'},{id:"B86",body:'Klenov MS et al. Impact of nuclear Piwi elimination on chromatin state in Drosophila melanogaster ovaries. Nucleic Acids Research. 2014;42(10):6208-6218. DOI: 10.1093/nar/gku268'},{id:"B87",body:'Lin H, Yin H. A novel epigenetic mechanism in Drosophila somatic cells mediated by Piwi and piRNAs. Cold Spring Harbor Symposia on Quantitative Biology. 2008;73:273-281. DOI: 10.1101/sqb.2008.73.056'},{id:"B88",body:'Sentmanat M, Wang SH, Elgin SC. Targeting heterochromatin formation to transposable elements in Drosophila: Potential roles of the piRNA system. Biochemistry (Moscow). 2013;78(6):562-571. DOI: 10.1134/S0006297913060023'},{id:"B89",body:'ElMaghraby MF et al. A heterochromatin-specific RNA export pathway facilitates piRNA production. Cell. 2019;178(4):964-979 e20. DOI: 10.1016/j.cell.2019.07.007'},{id:"B90",body:'Olszak AM et al. Heterochromatin boundaries are hotspots for de novo kinetochore formation. Nature Cell Biology. 2011;13(7):799-808. DOI: 10.1038/ncb2272'},{id:"B91",body:'Kwenda L, Collins CM, Dattoli AA, Dunleavy EM. Nucleolar activity and CENP-C regulate CENP-A and CAL1 availability for centromere assembly in meiosis. Development. 2016;143(8):1400-1412. DOI: 10.1242/dev.130625'},{id:"B92",body:'Bobkov GOM, Gilbert N, Heun P. Centromere transcription allows CENP-A to transit from chromatin association to stable incorporation. The Journal of Cell Biology. 2018;217(6):1957-1972. DOI: 10.1083/jcb.201611087'},{id:"B93",body:'Bobkov GOM et al. Spt6 is a maintenance factor for centromeric CENP-A. Nature Communications. 2020;11(1):2919. DOI: 10.1038/s41467-020-16695-7'},{id:"B94",body:'Jansen LE, Black BE, Foltz DR, Cleveland DW. Propagation of centromeric chromatin requires exit from mitosis. The Journal of Cell Biology. 2007;176(6):795-805. DOI: 10.1083/jcb.200701066'},{id:"B95",body:'Hemmerich P, Weidtkamp-Peters S, Hoischen C, Schmiedeberg L, Erliandri I, Diekmann S. Dynamics of inner kinetochore assembly and maintenance in living cells (in eng). The Journal of Cell Biology. 2008;180(6):1101-1114. DOI: 10.1083/jcb.200710052'},{id:"B96",body:'Schuh M, Lehner CF, Heidmann S. Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase. Current Biology. 2007;17(3):237-243. DOI: 10.1016/j.cub.2006.11.051'},{id:"B97",body:'Ahmad K, Henikoff S. Centromeres are specialized replication domains in heterochromatin. The Journal of Cell Biology. 2001;153(1):101-110. DOI: 10.1083/jcb.153.1.101'},{id:"B98",body:'Mellone BG, Grive KJ, Shteyn V, Bowers SR, Oderberg I, Karpen GH. Assembly of Drosophila centromeric chromatin proteins during mitosis. PLoS Genetics. 2011;7(5):e1002068. DOI: 10.1371/journal.pgen.1002068'},{id:"B99",body:'Pauleau AL, Erhardt S. Centromere regulation: New players, new rules, new questions. European Journal of Cell Biology. 2011;90(10):805-810. DOI: 10.1016/j.ejcb.2011.04.016'},{id:"B100",body:'Dunleavy EM, Beier NL, Gorgescu W, Tang J, Costes SV, Karpen GH. The cell cycle timing of centromeric chromatin assembly in Drosophila meiosis is distinct from mitosis yet requires CAL1 and CENP-C. PLoS Biology. 2012;10(12):e1001460. DOI: 10.1371/journal.pbio.1001460.'},{id:"B101",body:'Erhardt S, Mellone BG, Betts CM, Zhang W, Karpen GH, Straight AF. Genome-wide analysis reveals a cell cycle-dependent mechanism controlling centromere propagation. The Journal of Cell Biology. 2008;183(5):805-818. DOI: 10.1083/jcb.200806038'},{id:"B102",body:'Chen CC et al. CAL1 is the Drosophila CENP-A assembly factor. The Journal of Cell Biology. 2014;204(3):313-329. DOI: 10.1083/jcb.201305036'},{id:"B103",body:'Rosin L, Mellone BG. Co-evolving CENP-A and CAL1 domains mediate centromeric CENP-A deposition across Drosophila species. Developmental Cell. 2016;37(2):136-147. DOI: 10.1016/j.devcel.2016.03.021'},{id:"B104",body:'Moree B, Meyer CB, Fuller CJ, Straight AF. CENP-C recruits M18BP1 to centromeres to promote CENP-A chromatin assembly. The Journal of Cell Biology. 2011;194(6):855-871. DOI: 10.1083/jcb.201106079'},{id:"B105",body:'Pauleau AL, Bergner A, Kajtez J, Erhardt S. The checkpoint protein Zw10 connects CAL1-dependent CENP-A centromeric loading and mitosis duration in Drosophila cells. PLoS Genetics. 2019;15(9):e1008380. DOI: 10.1371/journal.pgen.1008380'},{id:"B106",body:'Demirdizen E et al. Localization of Drosophila CENP-A to non-centromeric sites depends on the NuRD complex. Nucleic Acids Research. 2019;47(22):11589-11608. DOI: 10.1093/nar/gkz962'},{id:"B107",body:'Roure V et al. Reconstituting Drosophila centromere identity in human cells. Cell Reports. 2019;29(2):464-479 e5. DOI: 10.1016/j.celrep.2019.08.067'},{id:"B108",body:'Medina-Pritchard B et al. Structural basis for centromere maintenance by Drosophila CENP-A chaperone CAL1. The EMBO Journal. 2020;39(7):e103234. DOI: 10.15252/embj.2019103234'},{id:"B109",body:'Williams BC, Murphy TD, Goldberg ML, Karpen GH. Neocentromere activity of structurally acentric mini-chromosomes in Drosophila. Nature Genetics. 1998;18(1):30-37. DOI: 10.1038/ng0198-30'},{id:"B110",body:'Wong LH, Saffery R, Choo KH. Construction of neocentromere-based human minichromosomes for gene delivery and centromere studies. Gene Therapy. 2002;9(11):724-726. DOI: 10.1038/sj.gt.3301756'},{id:"B111",body:'Choo KH. Domain organization at the centromere and neocentromere. Developmental Cell. 2001;1(2):165-177. DOI: 10.1016/s1534-5807(01)00028-4'},{id:"B112",body:'Moreno-Moreno O, Torras-Llort M, Azorin F. Proteolysis restricts localization of CID, the centromere-specific histone H3 variant of Drosophila, to centromeres. Nucleic Acids Research. 2006;34(21):6247-6255. DOI: 10.1093/nar/gkl902'},{id:"B113",body:'Heun P, Erhardt S, Blower MD, Weiss S, Skora AD, Karpen GH. Mislocalization of the Drosophila centromere-specific histone CID promotes formation of functional ectopic kinetochores. Developmental Cell. 2006;10(3):303-315. DOI: 10.1016/j.devcel.2006.01.014'},{id:"B114",body:'Palladino J, Chavan A, Sposato A, Mason TD, Mellone BG. Targeted de novo centromere formation in Drosophila reveals plasticity and maintenance potential of CENP-A chromatin. Developmental Cell. 2020;52(3):379-394 e7. DOI: 10.1016/j.devcel.2020.01.005'},{id:"B115",body:'Niikura Y, Kitagawa R, Kitagawa K. CENP-A ubiquitylation Is Inherited through dimerization between cell divisions. Cell Reports. 2016;15(1):61-76. DOI: 10.1016/j.celrep.2016.03.010'},{id:"B116",body:'Niikura Y, Kitagawa R, Fang L, Kitagawa K. CENP-A ubiquitylation is indispensable to cell viability. Developmental Cell. 2019;50(6):683-689 e6. DOI: 10.1016/j.devcel.2019.07.015'},{id:"B117",body:'Niikura Y, Kitagawa R, Kitagawa K. CENP-A ubiquitylation is required for CENP-A deposition at the centromere. Developmental Cell. 2017;40(1):7-8. DOI: 10.1016/j.devcel.2016.12.020'},{id:"B118",body:'Moreno-Moreno O, Medina-Giro S, Torras-Llort M, Azorin F. The F box protein partner of paired regulates stability of Drosophila centromeric histone H3, CenH3(CID). Current Biology. 2011;21(17):1488-1493. DOI: 10.1016/j.cub.2011.07.041'},{id:"B119",body:'Warburton PE et al. Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres. Current Biology. 1997;7(11):901-904. DOI: 10.1016/s0960-9822(06)00382-4'},{id:"B120",body:'Fujita R et al. Stable complex formation of CENP-B with the CENP-A nucleosome. Nucleic Acids Research. 2015;43(10):4909-4922. DOI: 10.1093/nar/gkv405'},{id:"B121",body:'Jing R et al. Motifs in the amino-terminus of CENP-A are required for its accumulation within the nucleus and at the centromere. Oncotarget. 2017;8(25):40654-40667. DOI: 10.18632/oncotarget.17204'},{id:"B122",body:'Shelby RD, Vafa O, Sullivan KF. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites. The Journal of Cell Biology. 1997;136(3):501-513. DOI: 10.1083/jcb.136.3.501'},{id:"B123",body:'Shelby RD, Monier K, Sullivan KF. Chromatin assembly at kinetochores is uncoupled from DNA replication. The Journal of Cell Biology. 2000;151(5):1113-1118. DOI: 10.1083/jcb.151.5.1113'},{id:"B124",body:'Bassett EA et al. HJURP uses distinct CENP-A surfaces to recognize and to stabilize CENP-A/histone H4 for centromere assembly. Developmental Cell. 2012;22(4):749-762. DOI: 10.1016/j.devcel.2012.02.001'},{id:"B125",body:'Hu H et al. Structure of a CENP-A-histone H4 heterodimer in complex with chaperone HJURP. Genes & Development. 2011;25(9):901-906. DOI: 10.1101/gad.2045111'},{id:"B126",body:'Yoda K, Tomonaga T. Centromere identity originates in the structure of CENP-A/H4 tetramer itself: A mechanism for aneuploidy. Lancet. 2004;364(9439):1022-1024. DOI: 10.1016/S0140-6736(04)17077-3'},{id:"B127",body:'Zhao H, Winogradoff D, Bui M, Dalal Y, Papoian GA. Promiscuous histone mis-assembly is actively prevented by chaperones. Journal of the American Chemical Society. 2016;138(40):13207-13218. DOI: 10.1021/jacs.6b05355'},{id:"B128",body:'Zhao H, Winogradoff D, Dalal Y, Papoian GA. The oligomerization landscape of histones. Biophysical Journal. 2019;116(10):1845-1855. DOI: 10.1016/j.bpj.2019.03.021'},{id:"B129",body:'Shang WH et al. Acetylation of histone H4 lysine 5 and 12 is required for CENP-A deposition into centromeres. Nature Communications. 2016;7:13465. DOI: 10.1038/ncomms13465'},{id:"B130",body:'Pan D, Walstein K, Take A, Bier D, Kaiser N, Musacchio A. Mechanism of centromere recruitment of the CENP-A chaperone HJURP and its implications for centromere licensing. Nature Communications. 2019;10(1):4046. DOI: 10.1038/s41467-019-12019-6'},{id:"B131",body:'Shuaib M, Ouararhni K, Dimitrov S, Hamiche A. HJURP binds CENP-A via a highly conserved N-terminal domain and mediates its deposition at centromeres. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(4):1349-1354. DOI: 10.1073/pnas.0913709107'},{id:"B132",body:'Bodor DL, Valente LP, Mata JF, Black BE, Jansen LE. Assembly in G1 phase and long-term stability are unique intrinsic features of CENP-A nucleosomes. Molecular Biology of the Cell. 2013;24(7):923-932. DOI: 10.1091/mbc.E13-01-0034'},{id:"B133",body:'Maddox PS, Hyndman F, Monen J, Oegema K, Desai A. Functional genomics identifies a Myb domain-containing protein family required for assembly of CENP-A chromatin. The Journal of Cell Biology. 2007;176(6):757-763. DOI: 10.1083/jcb.200701065'},{id:"B134",body:'McKinley KL, Cheeseman IM. Polo-like kinase 1 licenses CENP-A deposition at centromeres. Cell. 2014;158(2):397-411. DOI: 10.1016/j.cell.2014.06.016'},{id:"B135",body:'Perpelescu M, Nozaki N, Obuse C, Yang H, Yoda K. Active establishment of centromeric CENP-A chromatin by RSF complex. The Journal of Cell Biology. 2009;185(3):397-407. DOI: 10.1083/jcb.200903088'},{id:"B136",body:'Lagana A, Dorn JF, De Rop V, Ladouceur AM, Maddox AS, Maddox PS. A small GTPase molecular switch regulates epigenetic centromere maintenance by stabilizing newly incorporated CENP-A. Nature Cell Biology. 2010;12(12):1186-1193. DOI: 10.1038/ncb2129'},{id:"B137",body:'Prendergast L, Sullivan KF. A GTPase switch maintains CENP-A at centromeric chromatin. Nature Cell Biology. 2010;12(12):1128-1130. DOI: 10.1038/ncb1210-1128'},{id:"B138",body:'Mitra S, Srinivasan B, Jansen LET. Stable inheritance of CENP-A chromatin: Inner strength versus dynamic control. The Journal of Cell Biology. 2020;219(10). DOI: 10.1083/jcb.202005099'},{id:"B139",body:'Conde e Silva N, Black BE, Sivolob A, Filipski J, Cleveland DW, Prunell A. CENP-A-containing nucleosomes: Easier disassembly versus exclusive centromeric localization. Journal of Molecular Biology. 2007;370(3):555-573. DOI: 10.1016/j.jmb.2007.04.064'},{id:"B140",body:'Obuse C, Yang H, Nozaki N, Goto S, Okazaki T, Yoda K. Proteomics analysis of the centromere complex from HeLa interphase cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of the CEN-complex, while BMI-1 is transiently co-localized with the centromeric region in interphase. Genes to Cells. 2004;9(2):105-120. DOI: 10.1111/j.1365-2443.2004.00705.x'},{id:"B141",body:'Lee J, Zhou P. DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase. Molecular Cell. 2007;26(6):775-780. DOI: 10.1016/j.molcel.2007.06.001'},{id:"B142",body:'Mouysset J et al. CRL4(RBBP7) is required for efficient CENP-A deposition at centromeres. Journal of Cell Science. 2015;128(9):1732-1745. DOI: 10.1242/jcs.162305'},{id:"B143",body:'Nye J, Sturgill D, Athwal R, Dalal Y. HJURP antagonizes CENP-A mislocalization driven by the H3.3 chaperones HIRA and DAXX. PLoS One. 2018;13(10):e0205948. DOI: 10.1371/journal.pone.0205948'},{id:"B144",body:'Shrestha RL et al. Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells. Oncotarget. 2017;8(29):46781-46800. DOI: 10.18632/oncotarget.18108'},{id:"B145",body:'Sharma AB, Dimitrov S, Hamiche A, Van Dyck E. Centromeric and ectopic assembly of CENP-A chromatin in health and cancer: Old marks and new tracks. Nucleic Acids Research. 2019;47(3):1051-1069. DOI: 10.1093/nar/gky1298'},{id:"B146",body:'Tomonaga T et al. Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Research. 2003;63(13):3511-3516. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12839935'},{id:"B147",body:'Valdivia MM, Hamdouch K, Ortiz M, Astola A. CENPA a genomic marker for centromere activity and human diseases. Current Genomics. 2009;10(5):326-335. DOI: 10.2174/138920209788920985'},{id:"B148",body:'Li Y et al. ShRNA-targeted centromere protein A inhibits hepatocellular carcinoma growth. PLoS One. 2011;6(3):e17794. DOI: 10.1371/journal.pone.0017794'},{id:"B149",body:'Mahlke MA, Nechemia-Arbely Y. Guarding the genome: CENP-A-chromatin in health and cancer. Genes (Basel). 2020;11(7). DOI: 10.3390/genes11070810'},{id:"B150",body:'Burgess RJ, Zhang Z. Histone chaperones in nucleosome assembly and human disease. Nature Structural & Molecular Biology. 2013;20(1):14-22. DOI: 10.1038/nsmb.2461'},{id:"B151",body:'Huang X, Liu J, Ma Q. Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines. FEBS Open Bio. 2020;10(10):2182-2190. DOI: 10.1002/2211-5463.12966'},{id:"B152",body:'Mahmud I, Liao D. DAXX in cancer: Phenomena, processes, mechanisms and regulation. Nucleic Acids Research. 2019;47(15):7734-7752. DOI: 10.1093/nar/gkz634'},{id:"B153",body:'Ricketts MD, Marmorstein R. 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FBW7 loss promotes chromosomal instability and tumorigenesis via cyclin E1/CDK2-mediated phosphorylation of CENP-A. Cancer Research. 2017;77(18):4881-4893. DOI: 10.1158/0008-5472.CAN-17-1240'},{id:"B158",body:'Gassmann R et al. An inverse relationship to germline transcription defines centromeric chromatin in C. elegans. Nature. 2012;484(7395):534-537. DOI: 10.1038/nature10973'},{id:"B159",body:'Raychaudhuri N, Dubruille R, Orsi GA, Bagheri HC, Loppin B, Lehner CF. Transgenerational propagation and quantitative maintenance of paternal centromeres depends on Cid/Cenp-A presence in Drosophila sperm. PLoS Biology. 2012;10(12):e1001434. DOI: 10.1371/journal.pbio.1001434'},{id:"B160",body:'Fukagawa T, Earnshaw WC. The centromere: Chromatin foundation for the kinetochore machinery. Developmental Cell. 2014;30(5):496-508. DOI: 10.1016/j.devcel.2014.08.016'},{id:"B161",body:'Marshall OJ, Chueh AC, Wong LH, Choo KH. Neocentromeres: New insights into centromere structure, disease development, and karyotype evolution. American Journal of Human Genetics. 2008;82(2):261-282. DOI: 10.1016/j.ajhg.2007.11.009'},{id:"B162",body:'Van Hooser AA et al. Specification of kinetochore-forming chromatin by the histone H3 variant CENP-A. Journal of Cell Science. 2001;114(Pt 19):3529-3542. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11682612'},{id:"B163",body:'Canzonetta C, Leo M, Guarino SR, Montanari A, Francisci S, Filetici P. SAGA complex and Gcn5 are necessary for respiration in budding yeast. Biochimica et Biophysica Acta. 2016;1863(12):3160-3168. DOI: 10.1016/j.bbamcr.2016.10.002'},{id:"B164",body:'Niikura Y, Kitagawa R, Ogi H, Kitagawa K. SGT1-HSP90 complex is required for CENP-A deposition at centromeres. Cell Cycle. 2017;16(18):1683-1694. DOI: 10.1080/15384101.2017.1325039'},{id:"B165",body:'Niikura Y, Kitagawa K. Functions of SGT1, a Co-chaperone. In: Kaur P, Asea AAA, editors. Heat Shock Protein 90 in Human Diseases and Disorders (Asea AA, Calderwood SK, editors. Heat Shock Proteins). Vol. 19. Switzerland AG: Springer Nature; 2019. ch. 16. pp. 317-370'},{id:"B166",body:'Kitagawa K, Skowyra D, Elledge SJ, Harper JW, Hieter P. SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Molecular Cell. 1999;4(1):21-33. DOI: 10.1016/s1097-2765(00)80184-7'},{id:"B167",body:'Niikura Y, Ohta S, Vandenbeldt KJ, Abdulle R, McEwen BF, Kitagawa K. 17-AAG, an Hsp90 inhibitor, causes kinetochore defects: A novel mechanism by which 17-AAG inhibits cell proliferation. Oncogene. 2006;25(30):4133-4146. DOI: 10.1038/sj.onc.1209461'},{id:"B168",body:'Bansal PK, Abdulle R, Kitagawa K. Sgt1 associates with Hsp90: An initial step of assembly of the core kinetochore complex. Molecular and Cellular Biology. 2004;24(18):8069-8079. DOI: 10.1128/MCB.24.18.8069-8079.2004'},{id:"B169",body:'Lingelbach LB, Kaplan KB. The interaction between Sgt1p and Skp1p is regulated by HSP90 chaperones and is required for proper CBF3 assembly. Molecular and Cellular Biology. 2004;24(20):8938-8950. DOI: 10.1128/MCB.24.20.8938-8950.2004'},{id:"B170",body:'Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nature Reviews. Cancer. 2010;10(8):537-549. DOI: 10.1038/nrc2887'},{id:"B171",body:'Ogi H et al. The oncogenic role of the cochaperone Sgt1. Oncogene. 2015;4:e149. DOI: 10.1038/oncsis.2015.12'},{id:"B172",body:'Dias DC, Dolios G, Wang R, Pan ZQ. CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(26):16601-16606. DOI: 10.1073/pnas.252646399'},{id:"B173",body:'Davies AE, Kaplan KB. Hsp90-Sgt1 and Skp1 target human Mis12 complexes to ensure efficient formation of kinetochore-microtubule binding sites. The Journal of Cell Biology. 2010;189(2):261-274. DOI: 10.1083/jcb.200910036'},{id:"B174",body:'Steensgaard P et al. Sgt1 is required for human kinetochore assembly. EMBO Reports. 2004;5(6):626-631. DOI: 10.1038/sj.embor.7400154'},{id:"B175",body:'Ohkuni K et al. Deposition of centromeric histone H3 variant CENP-A/Cse4 into chromatin is facilitated by its C-terminal sumoylation. Genetics. 2020;214(4):839-854. DOI: 10.1534/genetics.120.303090'},{id:"B176",body:'Mukhopadhyay D, Arnaoutov A, Dasso M. The SUMO protease SENP6 is essential for inner kinetochore assembly. The Journal of Cell Biology. 2010;188(5):681-692. DOI: 10.1083/jcb.200909008'},{id:"B177",body:'Jentsch S, Psakhye I. Control of nuclear activities by substrate-selective and protein-group SUMOylation. Annual Review of Genetics. 2013;47:167-186. DOI: 10.1146/annurev-genet-111212-133453'},{id:"B178",body:'Liebelt F et al. The poly-SUMO2/3 protease SENP6 enables assembly of the constitutive centromere-associated network by group deSUMOylation. Nature Communications. 2019;10(1):3987. DOI: 10.1038/s41467-019-11773-x'},{id:"B179",body:'Mitra S et al. Genetic screening identifies a SUMO protease dynamically maintaining centromeric chromatin. Nature Communications. 2020;11(1):501. DOI: 10.1038/s41467-019-14276-x'},{id:"B180",body:'Kiyotaka N, Jason W, Cory H, Jiming J, Minoru M. Structure and evolution of plant centromeres. In: Ugarkovic D, editor. Centromere (Progress in Molecular and Subcellular Biology). Springer-Verlag Berlin Heidelbarg; 2009. pp. 153-179 ch. 6. DOI: 10.1007/978-3-642-00182-6_6'},{id:"B181",body:'Nagaki K et al. Molecular and cytological analyses of large tracks of centromeric DNA reveal the structure and evolutionary dynamics of maize centromeres. Genetics. 2003;163(2):759-770. DOI: 10.1093/genetics/163.2.759'},{id:"B182",body:'Du Y, Topp CN, Dawe RK. DNA binding of centromere protein C (CENPC) is stabilized by single-stranded RNA. PLoS Genetics. 2010;6(2):e1000835. DOI: 10.1371/journal.pgen.1000835'},{id:"B183",body:'Comai L, Maheshwari S, Marimuthu MPA. Plant centromeres. Current Opinion in Plant Biology. 2017;36:158-167. DOI: 10.1016/j.pbi.2017.03.003'},{id:"B184",body:'Oliveira LC, Torres GA. Plant centromeres: Genetics, epigenetics and evolution. Molecular Biology Reports. 2018;45(5):1491-1497. DOI: 10.1007/s11033-018-4284-7'},{id:"B185",body:'McClintock B. The significance of responses of the genome to challenge. Science. 1984;226(4676):792-801. DOI: 10.1126/science.15739260'},{id:"B186",body:'Zeitlin SG et al. Double-strand DNA breaks recruit the centromeric histone CENP-A. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(37):15762-15767. DOI: 10.1073/pnas.0908233106'},{id:"B187",body:'Cooper JL, Henikoff S. Adaptive evolution of the histone fold domain in centromeric histones. Molecular Biology and Evolution. 2004;21(9):1712-1718. DOI: 10.1093/molbev/msh179'},{id:"B188",body:'Talbert PB, Bryson TD, Henikoff S. Adaptive evolution of centromere proteins in plants and animals. Journal of Biology. 2004;3(4):18. DOI: 10.1186/jbiol11'},{id:"B189",body:'Malik HS, Henikoff S. Adaptive evolution of Cid, a centromere-specific histone in Drosophila. Genetics. 2001;157(3):1293-1298. DOI: 10.1093/genetics/157.3.1293'},{id:"B190",body:'Talbert PB, Masuelli R, Tyagi AP, Comai L, Henikoff S. Centromeric localization and adaptive evolution of an Arabidopsis histone H3 variant. Plant Cell. 2002;14(5):1053-1066. DOI: 10.1105/tpc.010425'},{id:"B191",body:'Sullivan BA, Schwartz S. Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres. Human Molecular Genetics. 1995;4(12):2189-2197. DOI: 10.1093/hmg/4.12.2189'},{id:"B192",body:'Murillo-Pineda M, Jansen LET. Genetics, epigenetics and back again: Lessons learned from neocentromeres. Experimental Cell Research. 2020;389(2):111909. DOI: 10.1016/j.yexcr.2020.111909'},{id:"B193",body:'Wang K, Wu Y, Zhang W, Dawe RK, Jiang J. Maize centromeres expand and adopt a uniform size in the genetic background of oat. Genome Research. 2014;24(1):107-116. DOI: 10.1101/gr.160887.113'},{id:"B194",body:'Henikoff S, Ahmad K, Malik HS. The centromere paradox: Stable inheritance with rapidly evolving DNA. Science. 2001;293(5532):1098-1102. DOI: 10.1126/science.1062939'},{id:"B195",body:'Hasson D et al. Formation of novel CENP-A domains on tandem repetitive DNA and across chromosome breakpoints on human chromosome 8q21 neocentromeres. Chromosoma. 2011;120(6):621-632. DOI: 10.1007/s00412-011-0337-6'},{id:"B196",body:'Gong Z et al. Repeatless and repeat-based centromeres in potato: Implications for centromere evolution. Plant Cell. 2012;24(9):3559-3574. DOI: 10.1105/tpc.112.100511'},{id:"B197",body:'Harrington JJ, Van Bokkelen G, Mays RW, Gustashaw K, Willard HF. Formation of de novo centromeres and construction of first-generation human artificial microchromosomes. Nature Genetics. 1997;15(4):345-355. DOI: 10.1038/ng0497-345'},{id:"B198",body:'Ananiev EV et al. Artificial chromosome formation in maize (Zea mays L.). Chromosoma. 2009;118(2):157-177. DOI: 10.1007/s00412-008-0191-3'},{id:"B199",body:'Phan BH et al. Transformation of rice with long DNA-segments consisting of random genomic DNA or centromere-specific DNA. Transgenic Research. 2007;16(3):341-351. DOI: 10.1007/s11248-006-9041-3'},{id:"B200",body:'Lermontova I, Schubert V, Fuchs J, Klatte S, Macas J, Schubert I. Loading of Arabidopsis centromeric histone CENH3 occurs mainly during G2 and requires the presence of the histone fold domain. Plant Cell. 2006;18(10):2443-2451. DOI: 10.1105/tpc.106.043174'},{id:"B201",body:'Sorge E, Demidov D, Lermontova I, Houben A, Conrad U. Engineered degradation of EYFP-tagged CENH3 via the 26S proteasome pathway in plants. PLoS One. 2021;16(2):e0247015. DOI: 10.1371/journal.pone.0247015'},{id:"B202",body:'Hsu PD et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nature Biotechnology. 2013;31(9):827-832. DOI: 10.1038/nbt.2647'},{id:"B203",body:'Biggins S. The composition, functions, and regulation of the budding yeast kinetochore. Genetics. 2013;194(4):817-846. DOI: 10.1534/genetics.112.145276'},{id:"B204",body:'Earnshaw WC, Rothfield N. Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma. Chromosoma. 1985;91(3-4):313-321. DOI: 10.1007/BF00328227'},{id:"B205",body:'Okada M et al. The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres. Nature Cell Biology. 2006;8(5):446-457. DOI: 10.1038/ncb1396'},{id:"B206",body:'Beh TT, Kalitsis P. Centromeres in health, disease and evolution. In: Felekkis K, Voskarides K, editors. Genomic Elements in Health, Disease and Evolution. New York: Springer Science+Business Media; 2015. pp. 221-244 ch. 9'},{id:"B207",body:'Burger A, Amemiya Y, Kitching R, Seth AK. Novel RING E3 ubiquitin ligases in breast cancer. Neoplasia. 2006;8(8):689-695. DOI: 10.1593/neo.06469'},{id:"B208",body:'Hu X et al. Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3. Cell Death & Disease. 2019;10(2):104. DOI: 10.1038/s41419-018-1200-y'},{id:"B209",body:'Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nature Medicine. 2013;19(11):1423-1437. DOI: 10.1038/nm.3394'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Yohei Niikura",address:"niikura@nicemice.cn",affiliation:'
MOE Key Laboratory of Model Animal for Disease Studies, Model Animal Research Center, School of Medicine, Nanjing University, China
Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, China
Department of Molecular Medicine, Greehey Children’s Cancer Research Institute, UT Health San Antonio, USA
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Abdurakhmonov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5940",title:"Vitamin C",subtitle:null,isOpenForSubmission:!1,hash:"e23e79359167bb9d4a53edd78c7b5038",slug:"vitamin-c",bookSignature:"Amal H. Hamza",coverURL:"https://cdn.intechopen.com/books/images_new/5940.jpg",editedByType:"Edited by",editors:[{id:"188326",title:"Associate Prof.",name:"Amal",middleName:null,surname:"Hamza",slug:"amal-hamza",fullName:"Amal Hamza"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:13,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"56013",doi:"10.5772/intechopen.69660",title:"Vitamin C: An Antioxidant Agent",slug:"vitamin-c-an-antioxidant-agent",totalDownloads:7788,totalCrossrefCites:26,totalDimensionsCites:57,abstract:"Vitamin C or ascorbic acid (AsA) is a naturally occurring organic compound with antioxidant properties, found in both animals and plants. It functions as a redox buffer which can reduce, and thereby neutralize, reactive oxygen species. It is a cofactor for enzymes involved in regulating photosynthesis, hormone biosynthesis, and regenerating other antioxidants; which also regulates cell division and growth, is involved in signal transduction, and has roles in several physiological processes, such as immune stimulation, synthesis of collagen, hormones, neurotransmitters, and iron absorption, has also roles in detoxifying the body of heavy metals. Severe deficiency of vitamin C causes scurvy, whereas limited vitamin C intake causes symptoms, such as increased susceptibility to infections, loosening of teeth, dryness of the mouth and eyes, loss of hair, dry itchy skin, fatigue, and insomnia. In contrast, vitamin C can also act as a prooxidant, especially in the presence of transition metals, such as iron and copper, starting different hazardous radical reactions. Vitamin C can both act as a strong, efficient, and cheap antioxidant agent and, at the same time, behave as a radical promoter. Further investigations are needed to illuminate the dual roles of vitamin C",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Fadime Eryılmaz Pehlivan",authors:[{id:"200567",title:"Dr.",name:"Fadime",middleName:null,surname:"Eryılmaz Pehlivan",slug:"fadime-eryilmaz-pehlivan",fullName:"Fadime Eryılmaz Pehlivan"}]},{id:"56440",doi:"10.5772/intechopen.70162",title:"Vitamin C: Sources, Functions, Sensing and Analysis",slug:"vitamin-c-sources-functions-sensing-and-analysis",totalDownloads:6400,totalCrossrefCites:14,totalDimensionsCites:26,abstract:"Vitamin C is a water-soluble compound found in living organisms. It is an essential nutrient for various metabolism in our body and also serves as a reagent for the preparation of many materials in the pharmaceutical and food industry. In this perspective, this chapter can develop interest and curiosity among all practicing scientists and technologists by expounding the details of its sources, chemistry, multifunctional properties and applications.",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Sudha J. Devaki and Reshma Lali Raveendran",authors:[{id:"187911",title:"Associate Prof.",name:"Sudha",middleName:null,surname:"J Devaki",slug:"sudha-j-devaki",fullName:"Sudha J Devaki"},{id:"204937",title:"Mrs.",name:"Reshma",middleName:null,surname:"Laly Ravindran",slug:"reshma-laly-ravindran",fullName:"Reshma Laly Ravindran"}]},{id:"50921",doi:"10.5772/63712",title:"Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet",slug:"menaquinones-bacteria-and-foods-vitamin-k2-in-the-diet",totalDownloads:3301,totalCrossrefCites:10,totalDimensionsCites:21,abstract:"Vitamin K2 is a collection of isoprenologues that mostly originate from bacterial synthesis, also called menaquinones (MKs). Multiple bacterial species used as starter cultures for food fermentation are known to synthesize MK. Therefore, fermented food is the best source of vitamin K2. In the Western diet, dairy products are one of the best known and most commonly consumed group of fermented products.",book:{id:"5169",slug:"vitamin-k2-vital-for-health-and-wellbeing",title:"Vitamin K2",fullTitle:"Vitamin K2 - Vital for Health and Wellbeing"},signatures:"Barbara Walther and Magali Chollet",authors:[{id:"184784",title:"Dr.",name:"Barbara",middleName:null,surname:"Walther",slug:"barbara-walther",fullName:"Barbara Walther"},{id:"188194",title:"Mrs.",name:"Magali",middleName:null,surname:"Chollet",slug:"magali-chollet",fullName:"Magali Chollet"}]},{id:"66098",doi:"10.5772/intechopen.84445",title:"Golden Rice: To Combat Vitamin A Deficiency for Public Health",slug:"golden-rice-to-combat-vitamin-a-deficiency-for-public-health",totalDownloads:3345,totalCrossrefCites:12,totalDimensionsCites:17,abstract:"Vitamin A deficiency (VAD) has been recognised as a significant public health problem continuously for more than 30 years, despite current interventions. The problem is particularly severe in populations where rice is the staple food and diversity of diet is limited, as white rice contains no micronutrients. Golden Rice is a public-sector product designed as an additional intervention for VAD. There will be no charge for the nutritional trait, which has been donated by its inventors for use in public-sector rice varieties to assist the resource poor, and no limitations on what small farmers can do with the crop—saving and replanting seed, selling seed and selling grain are all possible. Because Golden Rice had to be created by introducing two new genes—one from maize and the other from a very commonly ingested soil bacterium—it has taken a long time to get from the laboratory to the field. Now it has been formally registered as safe as food, feed, or in processed form by four industrialised counties, and applications are pending in developing countries. The data are summarised here, and criticisms addressed, for a public health professional audience: is it needed, will it work, is it safe and is it economic? Adoption of Golden Rice, the next step after in-country registration, requires strategic and tactical cooperation across professions, non-governmental organisations (NGOs) and government departments often not used to working together. Public health professionals need to play a prominent role.",book:{id:"7978",slug:"vitamin-a",title:"Vitamin A",fullTitle:"Vitamin A"},signatures:"Adrian Dubock",authors:[{id:"273220",title:"Ph.D.",name:"Adrian",middleName:null,surname:"Dubock",slug:"adrian-dubock",fullName:"Adrian Dubock"}]},{id:"62836",doi:"10.5772/intechopen.79350",title:"The Role of Thiamine in Plants and Current Perspectives in Crop Improvement",slug:"the-role-of-thiamine-in-plants-and-current-perspectives-in-crop-improvement",totalDownloads:1557,totalCrossrefCites:7,totalDimensionsCites:11,abstract:"Current research is focusing on selecting potential genes that can alleviate stress and produce disease-tolerant crop variety. The novel paradigm is to investigate the potential of thiamine as a crop protection molecule in plants. Thiamine or vitamin B1 is important for primary metabolism for all living organisms. The active form, thiamine pyrophosphate (TPP), is a cofactor for the enzymes involved in the synthesis of amino acids, tricarboxylic acid cycle and pentose phosphate pathway. Recently, thiamine is shown to have a role in the processes underlying protection of plants against biotic and abiotic stresses. The aim of this chapter is to review the role of thiamine in plant growth and disease protection and also to highlight that TPP and its intermediates are involved in management of stress. The perspectives on its potential for manipulating the biosynthesis pathway in crop improvement will also be discussed.",book:{id:"6709",slug:"b-group-vitamins-current-uses-and-perspectives",title:"B Group Vitamins",fullTitle:"B Group Vitamins - Current Uses and Perspectives"},signatures:"Atiqah Subki, Aisamuddin Ardi Zainal Abidin and Zetty Norhana\nBalia Yusof",authors:[{id:"240031",title:"Dr.",name:"Zetty-Norhana Balia",middleName:null,surname:"Yusof",slug:"zetty-norhana-balia-yusof",fullName:"Zetty-Norhana Balia Yusof"},{id:"261167",title:"Mr.",name:"Aisamuddin Ardi",middleName:null,surname:"Zainal Abidin",slug:"aisamuddin-ardi-zainal-abidin",fullName:"Aisamuddin Ardi Zainal Abidin"},{id:"261169",title:"Ms.",name:"Atiqah",middleName:null,surname:"Subki",slug:"atiqah-subki",fullName:"Atiqah Subki"}]}],mostDownloadedChaptersLast30Days:[{id:"56440",title:"Vitamin C: Sources, Functions, Sensing and Analysis",slug:"vitamin-c-sources-functions-sensing-and-analysis",totalDownloads:6391,totalCrossrefCites:14,totalDimensionsCites:25,abstract:"Vitamin C is a water-soluble compound found in living organisms. It is an essential nutrient for various metabolism in our body and also serves as a reagent for the preparation of many materials in the pharmaceutical and food industry. In this perspective, this chapter can develop interest and curiosity among all practicing scientists and technologists by expounding the details of its sources, chemistry, multifunctional properties and applications.",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Sudha J. Devaki and Reshma Lali Raveendran",authors:[{id:"187911",title:"Associate Prof.",name:"Sudha",middleName:null,surname:"J Devaki",slug:"sudha-j-devaki",fullName:"Sudha J Devaki"},{id:"204937",title:"Mrs.",name:"Reshma",middleName:null,surname:"Laly Ravindran",slug:"reshma-laly-ravindran",fullName:"Reshma Laly Ravindran"}]},{id:"56013",title:"Vitamin C: An Antioxidant Agent",slug:"vitamin-c-an-antioxidant-agent",totalDownloads:7779,totalCrossrefCites:26,totalDimensionsCites:55,abstract:"Vitamin C or ascorbic acid (AsA) is a naturally occurring organic compound with antioxidant properties, found in both animals and plants. It functions as a redox buffer which can reduce, and thereby neutralize, reactive oxygen species. It is a cofactor for enzymes involved in regulating photosynthesis, hormone biosynthesis, and regenerating other antioxidants; which also regulates cell division and growth, is involved in signal transduction, and has roles in several physiological processes, such as immune stimulation, synthesis of collagen, hormones, neurotransmitters, and iron absorption, has also roles in detoxifying the body of heavy metals. Severe deficiency of vitamin C causes scurvy, whereas limited vitamin C intake causes symptoms, such as increased susceptibility to infections, loosening of teeth, dryness of the mouth and eyes, loss of hair, dry itchy skin, fatigue, and insomnia. In contrast, vitamin C can also act as a prooxidant, especially in the presence of transition metals, such as iron and copper, starting different hazardous radical reactions. Vitamin C can both act as a strong, efficient, and cheap antioxidant agent and, at the same time, behave as a radical promoter. Further investigations are needed to illuminate the dual roles of vitamin C",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Fadime Eryılmaz Pehlivan",authors:[{id:"200567",title:"Dr.",name:"Fadime",middleName:null,surname:"Eryılmaz Pehlivan",slug:"fadime-eryilmaz-pehlivan",fullName:"Fadime Eryılmaz Pehlivan"}]},{id:"69402",title:"Vitamin D Deficiency and Diabetes Mellitus",slug:"vitamin-d-deficiency-and-diabetes-mellitus",totalDownloads:1578,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Vitamin D (VD) is a molecule that can be synthesized directly in the humans’ body or enter the organism with food in the form of inactive precursors. To exert its biological action, VD undergoes two-stage hydroxylation (at the 25th and 1st position) catalyzed by cytochromes P450, the presence of which has already been shown in almost all tissues of the human body. The product of hydroxylation is hormone-active form of vitamin D–1,25(OH)2D. 1,25(OH)2D binds to specific vitamin D receptor (VDR) and regulates the expression of genes involved in bone remodeling (classical function) and genes that control immune response, hormone secretion, cell proliferation, and differentiation (nonclassical functions). VD deficiency is prevalent around the globe and may be one of the key factors for diabetes development. The direct association between vitamin D deficiency and type 1 (T1D) and type 2 (T2D) diabetes has been proven. Detection of VDR in pancreas and adipose tissue, skeletal muscles, and immune cells allowed implying the antidiabetic role of vitamin D by enhancing insulin synthesis and exocytosis, increasing the expression of the insulin receptor, and modulating immune cells’ functions. This chapter summarizes data about relationship between VD insufficiency/deficiency and development of T1D and T2D, and their complications.",book:{id:"7038",slug:"vitamin-d-deficiency",title:"Vitamin D Deficiency",fullTitle:"Vitamin D Deficiency"},signatures:"Ihor Shymanskyi, Olha Lisakovska, Anna Mazanova and Mykola Veliky",authors:null},{id:"76108",title:"Vitamin D Metabolism",slug:"vitamin-d-metabolism",totalDownloads:460,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Vitamin D plays an important role in bone metabolism. Vitamin D is a group of biologically inactive, fat-soluble prohormones that exist in two major forms: ergocalciferol (vitamin D2) produced by plants in response to ultraviolet irradiation and cholecalciferol (vitamin D3) derived from animal tissues or 7-dehydrocholesterol in human skin by the action of ultraviolet rays present in sunlight. Vitamin D, which is biologically inactive, needs two-step hydroxylation for activation. All of these steps are of crucial for Vitamin D to show its effect properly. In this section, we will present vitamin D synthesis and its action steps in detail.",book:{id:"10631",slug:"vitamin-d",title:"Vitamin D",fullTitle:"Vitamin D"},signatures:"Sezer Acar and Behzat Özkan",authors:[{id:"29878",title:"Dr.",name:"Behzat",middleName:null,surname:"Özkan",slug:"behzat-ozkan",fullName:"Behzat Özkan"},{id:"348287",title:"Dr.",name:"Sezer",middleName:null,surname:"Acar",slug:"sezer-acar",fullName:"Sezer Acar"}]},{id:"50754",title:"Medicinal Chemistry of Vitamin K Derivatives and Metabolites",slug:"medicinal-chemistry-of-vitamin-k-derivatives-and-metabolites",totalDownloads:1904,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Vitamin K acts as a cofactor for γ‐glutamyl carboxylase. Recently, various biological activities of vitamin K have been reported. Anti‐proliferative activities of vitamin K, especially in vitamin K3, are well known. In addition, various physiological and pharmacological functions of vitamin K2, such as transcription modulators as nuclear steroid and xenobiotic receptor (SXR) ligands and anti‐inflammatory effects, have been revealed in the past decade. Characterization of vitamin K metabolites is also important for clinical application of vitamin K and its derivatives. In this chapter, recent progress on the medicinal chemistry of vitamin K derivatives and metabolites is discussed.",book:{id:"5169",slug:"vitamin-k2-vital-for-health-and-wellbeing",title:"Vitamin K2",fullTitle:"Vitamin K2 - Vital for Health and Wellbeing"},signatures:"Shinya Fujii and Hiroyuki Kagechika",authors:[{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika"},{id:"180529",title:"Dr.",name:"Shinya",middleName:null,surname:"Fujii",slug:"shinya-fujii",fullName:"Shinya Fujii"}]}],onlineFirstChaptersFilter:{topicId:"42",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81286",title:"Potassium Derangements: A Pathophysiological Review, Diagnostic Approach, and Clinical Management",slug:"potassium-derangements-a-pathophysiological-review-diagnostic-approach-and-clinical-management",totalDownloads:41,totalDimensionsCites:0,doi:"10.5772/intechopen.103016",abstract:"Potassium is an essential cation critical in fluid and electrolyte balance, acid–base regulation, and neuromuscular functions. The normal serum potassium is kept within a narrow range of 3.5–5.2 meq/L while the intracellular concentration is approximately 140–150 meq/L. The total body potassium is about 45–55 mmol/kg; thus, a 70 kg male has an estimated ~136 g and 60 kg female has ~117 g of potassium. In total, 98% of the total body potassium is intracellular. Skeletal muscle contains ~80% of body potassium stores. The ratio of intracellular to extracellular potassium concentration (Ki/Ke) maintained by Na+/K+ ATPase determines the resting membrane potential. Disturbances of potassium homeostasis lead to hypo- and hyperkalemia, which if severe, can be life-threatening. Prompt diagnosis and management of these problems are important.",book:{id:"10794",title:"Potassium in Human Health",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg"},signatures:"Sairah Sharif and Jie Tang"},{id:"79194",title:"Potassium in Solid Cancers",slug:"potassium-in-solid-cancers",totalDownloads:157,totalDimensionsCites:0,doi:"10.5772/intechopen.101108",abstract:"Electrolyte disorders are a frequent finding in cancer patients. In the majority of cases the etiologies of such disorders are common to all cancer types (i.e. diuretic-induced hyponatremia or hypokalemia). Sometimes, electrolyte disorders are caused by paraneoplastic syndromes or are due to cancer therapy. Potassium is one of the most important electrolytes of the human body since it is involved in the regulation of muscle contraction, maintenance of the integrity of the skeleton, blood pressure and nerve transmission as well as in the normal function of cells. Potassium homeostasis is strictly regulated since the gap between the recommended daily dietary intake (120 mEq/day) and the levels stored in the extracellular fluid (around 70 mEq) is huge. Alterations of potassium homeostasis are frequent in cancer patients as well alterations in potassium channels, the transmembrane proteins that mediate potassium fluxes within the cells. The present chapter is focused on the clinical significance of potassium homeostasis and potassium channels in patients with solid tumors.",book:{id:"10794",title:"Potassium in Human Health",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg"},signatures:"Jessica Iorio, Lisa Lastraioli and Elena Lastraioli"},{id:"78820",title:"Potassium Homeostasis",slug:"potassium-homeostasis",totalDownloads:120,totalDimensionsCites:0,doi:"10.5772/intechopen.100368",abstract:"The average potassium intake in the United States population ranges from 90 to 120 mEq/day. About 98% of the total body’s potassium is intracellular, and only 2% is present in the extracellular compartment. This distributional proportion is essential for cellular metabolic reactions and maintaining a gradient for resting membrane potential. A loss of this gradient results in hyper- or hypopolarization of the cell membrane, especially in cardiac muscles leading to life-threatening arrhythmias. Multiple mechanisms in human maintain homeostasis. Transient initial changes are due to transcellular shifts activating sodium-potassium ATPase pumps on the cell membrane. The kidneys essentially take part in excess potassium excretion, maintaining total body stores constant within normal range. Gastrointestinal secretion of potassium is insignificant in individuals with normal renal function, however plays an essential role in individuals with compromised renal function. So far, a classic feedback mechanism was thought to maintain potassium homeostasis; however, a recently recognized feedforward mechanism acting independently also helps preserve potassium homeostasis. Hence, potassium homeostasis is vital for humans to function at a normal level.",book:{id:"10794",title:"Potassium in Human Health",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg"},signatures:"Shakuntala S. Patil and Sachin M. Patil"},{id:"78193",title:"Potassium and Cardiac Surgery",slug:"potassium-and-cardiac-surgery",totalDownloads:203,totalDimensionsCites:1,doi:"10.5772/intechopen.99735",abstract:"Potassium homeostasis affects cardiac rhythm and contractility, along with vascular reactivity and vascular smooth muscle proliferation. This chapter will focus on potassium dynamics during and after cardiac surgery involving cardioplegic arrest and cardiopulmonary bypass (CPB). Hyperkalemic, hypothermic solutions are frequently used to induce cardioplegic arrest and protect the heart during cardiac surgery involving CPB. Common consequences of hyperkalemic cardioplegic arrest and reperfusion include microvascular dysfunction involving several organ systems and myocardial dysfunction. Immediately after CPB, blood potassium levels often drop precipitously due to a variety of factors, including CPB -induced electrolyte depletion and frequent, long-term administration of insulin during and after surgery. Meanwhile, some patients with pre-existing kidney dysfunction may experience postoperative hyperkalemia following cardioplegia. Any degree of postoperative hyper/hypokalemia significantly elevates the risk of cardiac arrythmias and subsequent myocardial failure. 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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:301,paginationItems:[{id:"116250",title:"Dr.",name:"Nima",middleName:null,surname:"Rezaei",slug:"nima-rezaei",fullName:"Nima Rezaei",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/116250/images/system/116250.jpg",biography:"Professor Nima Rezaei obtained an MD from Tehran University of Medical Sciences, Iran. He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. 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