E3 ligase for budding yeast (
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6493",leadTitle:null,fullTitle:"Psychotic Disorders - An Update",title:"Psychotic Disorders",subtitle:"An Update",reviewType:"peer-reviewed",abstract:"In this book, with the involvement not only of clinical psychiatrists but also of neurobiologists, specific issues of psychotic disorders (mainly schizophrenia and mood disorders) are reviewed. The focus of attention ranges from therapeutics to the new frontiers of epigenetics. A special focus is on the individual reactions to psychosis (ranging from psychological ones to treatments and neurobiological basis). Because of the rapid development of neurosciences, which are showing common underling factors to different phenotypical expressions of mental illness, we are facing an enormous growth of biological data, which is not always easy to interpret. The risk is to forget that we are relating to other individuals, with their stories, and, most of all, with their environmental resources and interactions. The contributions to this book will range from individual experience (a personal history of illness) through some aspects of individual management of illness (insight), from correct use of available psychosocial resources to the environment-gene relationships (epigenetics).",isbn:"978-1-78923-325-4",printIsbn:"978-1-78923-324-7",pdfIsbn:"978-1-83881-500-4",doi:"10.5772/intechopen.70973",price:119,priceEur:129,priceUsd:155,slug:"psychotic-disorders-an-update",numberOfPages:172,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"10c61c9adb13a7f0780176f556353b2e",bookSignature:"Federico Durbano",publishedDate:"June 27th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6493.jpg",numberOfDownloads:9396,numberOfWosCitations:6,numberOfCrossrefCitations:5,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:14,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:25,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 20th 2017",dateEndSecondStepPublish:"October 11th 2017",dateEndThirdStepPublish:"December 10th 2017",dateEndFourthStepPublish:"February 28th 2018",dateEndFifthStepPublish:"April 29th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"157077",title:"Dr.",name:"Federico",middleName:null,surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano",profilePictureURL:"https://mts.intechopen.com/storage/users/157077/images/system/157077.jpeg",biography:"Dr. Federico Durbano received a degree in Medicine with a specialization in Psychiatry. He has worked at various hospitals, including Milan “Ospedale Maggiore Policlinico,” Treviglio, Melegnano, and Fatebenefratelli, where he achieved significant career milestones. He is currently the director of the Mental Health and Substance Abuse Department at ASST Melegnano e della Martesana. Dr. Durbano has had teaching assignments at the University of Milan (Nursing School) and the University of Castellanza (Master in Criminology). He has attended more than seventy local and national congresses and courses as an invited speaker and has published more than 180 papers. He is also a technical advisor to the court in the field of forensic psychiatry.",institutionString:"Mental Health and Substance Abuse Department in ASST Melegnano and Martesana",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"ASST Melegnano e della Martesana",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1061",title:"Psychiatry",slug:"mental-and-behavioural-disorders-and-diseases-of-the-nervous-system-psychiatry"}],chapters:[{id:"61322",title:"Introductory Chapter: Unmet Needs and Future Developments",doi:"10.5772/intechopen.77325",slug:"introductory-chapter-unmet-needs-and-future-developments",totalDownloads:954,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Federico Durbano",downloadPdfUrl:"/chapter/pdf-download/61322",previewPdfUrl:"/chapter/pdf-preview/61322",authors:[{id:"157077",title:"Dr.",name:"Federico",surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"}],corrections:null},{id:"58826",title:"Descent into Darkness",doi:"10.5772/intechopen.72602",slug:"descent-into-darkness",totalDownloads:998,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This personal narrative of a time with schizophrenia will cover one patient’s descent into madness and ultimate recovery from a period that felt like a sentence in a prison of hell and irrationality. Following a breakdown that led to the patient’s withdrawal from graduate school, this narrative covers the experience of madness that led to delusions and hallucinations which tyrannized the patient’s world. The narrative not only follows the breakdown of humanity that cursed the patient’s understanding but also provides for the highlights of recovery that brought about a return to intellectual activities and a full comprehension of experience in the world. Though this patient’s life was destroyed by schizophrenia, including the loss of all worldly goods and a career in academia, her experience of caring psychiatrists and a loving family redeemed her life and brought about solace and renewal at last.",signatures:"Susan Weiner",downloadPdfUrl:"/chapter/pdf-download/58826",previewPdfUrl:"/chapter/pdf-preview/58826",authors:[{id:"222909",title:"Ms.",name:"Susan",surname:"Weiner",slug:"susan-weiner",fullName:"Susan Weiner"}],corrections:null},{id:"60685",title:"Lack of Insight in Bipolar Disorder: The Impact on Treatment Adherence, Adverse Clinical Outcomes and Quality of Life",doi:"10.5772/intechopen.76286",slug:"lack-of-insight-in-bipolar-disorder-the-impact-on-treatment-adherence-adverse-clinical-outcomes-and-",totalDownloads:1291,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Insight is a multidimensional construct, defined as the awareness of having a mental disorder, of specific symptoms and their attribution to the disorder, the awareness of social consequences, and of need for treatment. Although insight has been studied specifically in schizophrenia and its study in mood disorders has traditionally received limited attention, the evaluation of this concept in mood disorders is also very important because of the impact on treatment compliance and outcome. In bipolar disorder (BD), clinical insight varies substantially over time. Most researchers observed that insight is more impaired during an illness episode than during remission, in mixed than in pure manic episodes, in bipolar II than in bipolar I patients, and in pure mania than in bipolar or unipolar depression. Lack of insight is a consistent factor of non-adherence to medication in bipolar patients, along with severity of BD, side effects of medication, effectiveness, and patient-related factors. Also, impaired insight into treatment and a great number of previous hospitalizations are associated with poorer clinical outcomes (psychiatric hospitalization, emergency room visits, violent or suicidal behavior) among the patients with bipolar I disorder. In the management of bipolar disorder, improving quality of life (QoL) and outcome should be one the most important goals.",signatures:"Cătălina Angela Crișan",downloadPdfUrl:"/chapter/pdf-download/60685",previewPdfUrl:"/chapter/pdf-preview/60685",authors:[{id:"215543",title:"Dr.",name:"Catalina",surname:"Crisan",slug:"catalina-crisan",fullName:"Catalina Crisan"}],corrections:null},{id:"58847",title:"Negative Symptoms of Schizophrenia: Constructs, Burden, and Management",doi:"10.5772/intechopen.73300",slug:"negative-symptoms-of-schizophrenia-constructs-burden-and-management",totalDownloads:1709,totalCrossrefCites:0,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The aim of the chapter is to raise awareness about recent constructs of negative symptoms, their burden on patients, caregivers and society, and about their management. Schizophrenia consists of positive, negative, and cognitive symptoms. However, treating physicians are not necessarily aware about recent constructs of negative symptoms, their presence at prodromal stage, and the distinction among primary, secondary, persistent, prominent, or predominant negative symptoms. Negative symptoms have a substantial impact on the day-to-day functioning of patients with schizophrenia and contribute more to impaired quality of life and poor functioning than positive symptoms do. Additionally, they are associated with high costs for society and a substantial burden for caregivers. Negative symptoms are not adequately treated by available antipsychotic therapies. Publications have shown that no antipsychotic has a beneficial effect when compared to another. Cariprazine is the only antipsychotic that has proven superiority over another antipsychotic (risperidone) in one clinical study.",signatures:"Agota Barabassy, Balázs Szatmári, István Laszlovszky and György\nNémeth",downloadPdfUrl:"/chapter/pdf-download/58847",previewPdfUrl:"/chapter/pdf-preview/58847",authors:[{id:"223610",title:"Dr.",name:"Agota",surname:"Barabassy",slug:"agota-barabassy",fullName:"Agota Barabassy"},{id:"239408",title:"Dr.",name:"Balázs",surname:"Szatmári",slug:"balazs-szatmari",fullName:"Balázs Szatmári"},{id:"239409",title:"Dr.",name:"István",surname:"Laszlovszky",slug:"istvan-laszlovszky",fullName:"István Laszlovszky"},{id:"239410",title:"Dr.",name:"György",surname:"Németh",slug:"gyorgy-nemeth",fullName:"György Németh"}],corrections:null},{id:"60964",title:"Interdisciplinary Rehabilitation to Facilitate Recovery of People Living with Long-Term Schizophrenia in Developing Countries",doi:"10.5772/intechopen.75548",slug:"interdisciplinary-rehabilitation-to-facilitate-recovery-of-people-living-with-long-term-schizophreni",totalDownloads:1208,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Schizophrenia is characterized by irregular, alternating episodes of exacerbation and remission of psychotic symptoms. The occupational care for people living with long-term schizophrenia (PLWS) after medical treatment, for re-engagement into work, leisure, and daily-living activities, still needs attention. Personalizing follow-up care of PLWS can improve the medical-psychosocial level of patient with differing medical, physical, and psychosocial effects from their treatment exposures. This chapter highlights the call for an individual care approach that is often lacking in resource-limited countries with additional burden from entrenched stigma. Patient categorization for PLWS may be a cost-effective step forward to overcome the less effective, one-size-fits-all approach. The need to address personalized assessment of risk exposure and to remediate its consequences on function, recovery, and quality of life calls for a better interdisciplinary-care approach, and a renewed investment to ensure occupational performance after recovery. Medicine is initial, but personalized rehabilitation is warranted for much improved functioning and better quality of life. Research is also needed to evaluate and document the effectiveness of various models of interdisciplinary care for PLWS that have been developed but may not be tested/evaluated and also on models tested effective but on other long-term nonphysical conditions.",signatures:"Siew Yim Loh",downloadPdfUrl:"/chapter/pdf-download/60964",previewPdfUrl:"/chapter/pdf-preview/60964",authors:[{id:"190912",title:"Associate Prof.",name:"Siew Yim",surname:"Loh",slug:"siew-yim-loh",fullName:"Siew Yim Loh"}],corrections:null},{id:"61813",title:"Genetics and Epigenetics of Schizophrenia",doi:"10.5772/intechopen.75930",slug:"genetics-and-epigenetics-of-schizophrenia",totalDownloads:1100,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Schizophrenia (SCZ) is a complex mental disorder, with a longstanding history of neurobiological investigation. It is more common in those persons who are genetically predisposed to the disorder. Since Kraepelin, psychiatrists were aware that the SCZ tended to run in families. Its heritability is up to 85%. Although the etiology of SCZ is unknown, it is now thought to be multifactorial, with multiple susceptibility genes interacting with environmental and developmental factors. There is a huge amount of genetic studies, including polymorphisms, expression, methylation, microRNAs, and epigenomics. However, identifying genes for SCZ using traditional genetic approaches has thus far proven quite difficult. Reasons for this include the complexity, heterogeneity, and comorbidity of this disorder, and also the poor definition of the clinical phenotype. Important approaches to find the relation between genotype and phenotype and may be causal genetic factors are endophenotypes and pathway analysis. However, genetic researchers need to consider carefully the models of causality they choose. There is a pathophysiological pathway that extends from genes, through proteins, neurons, neural circuits, neural regions, mental functions, external behaviors, and symptoms of SCZ. In this chapter, the genetics and epigenetics of SCZ are briefly discussed.",signatures:"Esmaeil Shahsavand Ananloo",downloadPdfUrl:"/chapter/pdf-download/61813",previewPdfUrl:"/chapter/pdf-preview/61813",authors:[{id:"225463",title:"Dr.",name:"Esmaeil",surname:"Shahsavand Ananloo",slug:"esmaeil-shahsavand-ananloo",fullName:"Esmaeil Shahsavand Ananloo"}],corrections:null},{id:"58952",title:"Immune System Dysregulation and Autoimmunity in Schizophrenia: IgGs from Sera of Patients with Several Catalytic Activities",doi:"10.5772/intechopen.73194",slug:"immune-system-dysregulation-and-autoimmunity-in-schizophrenia-iggs-from-sera-of-patients-with-severa",totalDownloads:964,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Schizophrenia is usually a progressive mental illness with very different polymorphic symptoms. Several different theories of schizophrenia were discussed; the causes of this disease are not yet clear. Destruction of DNA, RNA, and myelin basic protein (MBP) by inflammation caused by autoimmune reactions has been revealed. Healthy humans usually do not develop abzymes. It was shown that DNase, RNase, and MBP-hydrolyzing abzymes are easily detectable at the beginning of different autoimmune diseases (AIDs). During the development of spontaneous and induced AIDs in mice, a specific reorganization of their immune system associated with the generation of abzymes hydrolyzing different autoantigens was revealed. SCZ is currently not assigned to classical autoimmune diseases. However, the sera of approximately 30% of SCZ patients demonstrated a high level of anti-DNA Abs (comparing to 37% of SLE patients); abzymes hydrolyzing DNA, RNA, and MBP were revealed in 80–100% of SCZ patients. The site-specific hydrolysis of four known SCZ-specific microRNA playing an important role in the regulation of several genes functioning was revealed. Anti-MBP IgGs hydrolyze specifically only MBP but not other proteins. The data indicate that SCZ patients may to a certain extent show similar to SLE and MS patients’ typical signs of autoimmune processes.",signatures:"Valentina N. Buneva, Evgeny A. Ermakov and Georgy A. Nevinsky",downloadPdfUrl:"/chapter/pdf-download/58952",previewPdfUrl:"/chapter/pdf-preview/58952",authors:[{id:"47119",title:"Dr.",name:"Georgy",surname:"Nevinsky",slug:"georgy-nevinsky",fullName:"Georgy Nevinsky"},{id:"178315",title:"Dr.",name:"Valentina",surname:"Buneva",slug:"valentina-buneva",fullName:"Valentina Buneva"},{id:"223509",title:"Mr.",name:"Evgeny",surname:"Ermakov",slug:"evgeny-ermakov",fullName:"Evgeny Ermakov"}],corrections:null},{id:"58976",title:"Epigenetic and Schizophrenia",doi:"10.5772/intechopen.73242",slug:"epigenetic-and-schizophrenia",totalDownloads:1181,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Schizophrenia is a complex psychiatric disorder characterised by the presence of positive, negative and cognitive symptoms that lack a unifying neuropathology. The absence of consistently replicated genetic effects, together with evidence for lasting changes in gene expression after environmental exposures, suggests a role of epigenetic mechanisms. In this chapter, we will focus on these mechanisms, such as DNA methylation, hydroxymethylation, histone modifications or non-coding RNA, as key mechanisms through which environmental factors interact with individual’s genetic constitution which affect the risk of psychotic conditions throughout life. 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In contrast to most eukaryotic centromeres that span megabases of DNA, in the budding yeast,
In
Early studies showed that Scm3 is required for G2/M progression and Cse4 localization at centromeres. Scm3 contains 2 essential protein domains: a Leu-rich nuclear export signals and a heptad repeat domain that is widely conserved in fungi [5, 6, 7, 8, 9, 10, 11]. Localization of Cse4 to centromeres and the assembly activity is dependent on an evolutionarily conserved central core motif in Scm3 [13]. Camahort et al. showed that Scm3 is required throughout the whole cell cycle as well as the loading period for Cse4 [5, 14]. Consistent with these findings, Xiao et al. showed that Scm3 has an N-terminal nonspecific DNA binding domain for AT-rich DNA and a central histone chaperone domain (Cse4/H4 binding domain, CBD) that promotes specific loading of Cse4/H4 [15]. Moreover, Xiao et al. demonstrated that Scm3-GFP is enriched at centromeres in all cell cycle phases in live cells, and their results of ChIP analysis showed that Scm3 occupies centromere DNA throughout the cell cycle, even when Cse4 and H4 are temporarily dislodged in the S phase, suggesting Scm3 is a critical factor for recruitment of Cse4/H4 as well as maintenance of an H2A/H2B-deficient centromeric nucleosome [15]. Luconi et al. showed that Scm3 signals are present at centromeres when metaphase begins, and enriched in anaphase [14, 16] as observed for Scm3 in fission yeast
Currently, the structure of budding yeast centromeric CENP-ACse4-containing nucleosomes remains controversial among different research groups as in other species [17]. Dechassa et al. performed structural analysis and showed that the substitution of H3 with Cse4 results in octameric nucleosomes that organize DNA in a left-handed superhelix [18]. Cse4-nucleosomes exhibit an open conformation with weakly bound terminal DNA segments and do not preferentially form nucleosomes on its cognate centromeric DNA. The Cse4-specific octameric nucleosomes do not contain Scm3 as a stably bound component. Cho et al. reported the structure of a complex formed by an N-terminal fragment of Scm3 with the histone-fold domains of Cse4, and H4, which were all purified from the budding yeast
Mechanistic scheme for
Recently, the importance of centromeric long non-coding RNA (cenRNA) for centromere integrity has been suggested in various species [35, 36, 37] including budding yeast [38, 39, 40]. Ling et al. reported that all the budding yeast centromere express long noncoding RNAs (cenRNAs), especially in S phase and induction of cenRNAs coincides with Cse4 loading time and is dependent on DNA replication [38]. The cenRNA is tightly regulated and repressed by the kinetochore protein Cbf1 and histone H2A variant H2A.ZHtz1, and de-repressed during the S phase of the cell cycle, suggesting that an appropriate level of cenRNAs is essential for point centromere activity [38]. Interestingly, when they knocked down all cenRNAs from the endogenous chromosomes, but not the cenRNA from the circular minichromosome, they still observed an increase in minichromosome loss, suggesting that cenRNA functions in trans to regulate centromere activity. Chen et al. independently demonstrated that budding yeast cenRNA is negatively regulated by Cbf1 and binding of the Pif1 DNA helicase to the centromeres, which happens in mid–late S phase, occurred at about the same time as Cbf1 loss from the centromere [40]. These data suggest that Pif1 may facilitate this loss by its known ability to displace proteins from DNA. Ling et al. further showed that budding yeast cenRNAs are cryptic unstable transcripts (CUTs) that can be degraded by the nuclear RNA decay pathway suggesting that cenRNA can serve important cellular functions when it exists at the right time with the right level [39]. Together, these results in budding yeast indicate that the regulation of cenRNA is an essential factor for centromere structure and function.
CENP-A (CenH3) proteolysis has also been reported in senescent human cells [41] or upon infection with herpes simplex virus 1 [42]. However, little had been known about the actual mechanisms that regulate CENP-A (CenH3) proteolysis. Collins et al. initially reported that the levels of the budding yeast CenH3, Cse4, are regulated by ubiquitin-proteasome-mediated proteolysis in 2004 [43]. They isolated a dominant lethal mutant,
lo | CENP-A homolog | E3 ligase (ubiquitylation or sumoylation) | Function | Preceding PTMs before ubiquitylation or sumoylation | Other proposed factor relevant to E3 function |
---|---|---|---|---|---|
Cse4 | Psh1 (ubiquitylation) | Proteasomal degradation to remove non-centromeric CENP-A | P134 isomerization by Fpr3 | Scm3, Snf2, Doa1, Fpr3, Spt16. Phosphorylation of Psh1 by Cka2, Pat1, Histone H4-R36, Gene dosage of histone H4 (HHF1 and HHF2), CAF-1, Hir2, Cdc7, Ubp8 (deubiquitylation, SAGA-DUB), Cse4 MIMAS motif | |
Slx5/8 (vertebrate RNF4)(ubiquitylation) | Proteasomal degradation to remove non-centromeric CENP-A (Slx5-mediated Cse4 proteolysis could be independent of Psh1) | K65 sumoylation by Siz1/2 | K65 sumoylation by Siz1/2 | ||
Siz1/2 (sumoylation) | Proteasomal degradation to remove non-centromeric CENP-A | N.D. | N.D. (The effect of SUMO-proteases Ulp2/SENP6, on CenH3 was not confirmed.) | ||
Ubr1, Rcy1 (ubiquitylation) | Proteasomal degradation of Cse4 | N.D. | N.D. | ||
Met30/Cdc4 (ubiquitylation) | Proteasomal degradation of Cse4 (Met30/Cdc4-mediated Cse4 proteolysis could be independent of Psh1) | N.D. | N.D. |
E3 ligase for budding yeast (
Hewawasam et al. performed TAP purification of Psh1 and identified Cse4 as well as several other kinetochore proteins by multidimensional protein identification technology analysis [22]. They described that Psh1 consists of three main domains: (i) a RING finger, (ii) a zinc finger, and (iii) a highly acidic domain [22, 23]. They performed co-immunoprecipitation using whole-cell extracts and showed that the RING finger of Psh1 is important to interact with Cse4. They also performed a pulse-chase assay and demonstrated that both RING and zinc fingers are critical for efficient control of Cse4 levels. They demonstrated the specificity of the ubiquitylation activity of Psh1 toward Cse4 in vitro and identified the sites of ubiquitylation. Mutation of these lysine sites prevents ubiquitylation of Cse4 by Psh1 in vitro and stabilizes Cse4 in vivo. Elimination of the Cse4-specific chaperone Scm3 destabilizes Cse4, and the addition of Scm3 to the Psh1-Cse4 ubiquitylation reaction prevents Cse4 ubiquitylation. Meanwhile, the deletion of Psh1 stabilizes Cse4. These data suggest that 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 [23] (Figure 1, right) (see also next chapter, section 4.2). Cse4 overexpression is toxic without Psh1, and Cse4 is found at ectopic locations. Therefore, they suggested that the E3 activity of Psh1 prevents the mislocalization of Cse4 (Figure 1, left).
Ranjitkar et al. also identified Psh1 by mass spectrometry analysis after purification of 3xFLAG-Cse416R that is not ubiquitylated in vivo [45]. They demonstrated that Cse4 overexpression causes growth defects on
However, the new findings of E3 ligase, Psh1, by these two groups left these open questions and stimulated other researchers to study the Psh1-mediated ubiquitylation and degradation of Cse4 as well as CENP-A homologs of other species.
Why does deletion of
No Psh1 ortholog in other eukaryotes is yet identified. Because the RING and zinc fingers are highly conserved motifs in many proteins from yeast to human, it is difficult to verify such an ortholog. It is also unclear whether the ubiquitin–proteasome pathway that controls CENP-A proteolysis is conserved among different species.
Can Psh1 be the unique E3 ligase in yeast? Is it possible to identify other E3 ligases that ubiquitylate Cse4 in the same or different function? Is the function of the Cse4 ubiquitylation restricted only to proteolysis?
Are any other post-translational modifications of Cse4 involved in upstream or downstream functions of Cse4 ubiquitylation?
What is the genome-wide misincorporation pattern of Cse4? How does the pattern change in the presence and absence of Psh1? Does Cse4 misincorporation affect promotor function and transcriptional regulation?
What is the molecular mechanism for the selective recognition and ubiquitylation of Cse4 by Psh1? Are other components required for such activities, or are other PTMs of Cse4 involved?
What are the deubiquitylase and deubiquitylation mechanisms of Cse4?
In the following sections, answers to some of these questions are further described.
Gkikopoulos et al. had identified DNA sequences to which the
The aforementioned groups had shown interactions of Psh1 with the C-terminus CATD of Cse4 and ubiquitylation of Cse4 at its C-terminus in vitro [22, 45]. Further, Au et al. demonstrated a role for ubiquitination of the N-terminus of Cse4 in regulating Cse4 proteolysis [47]. They initiated their studies with a mutant
Ohkuni et al. reported that the proline isomerase Fpr3 regulates Cse4 proteolysis [32] (Figure 1 and Table 1).
Deyter et al. identified a role for the conserved chromatin-modifying complex FACT (facilitates chromatin transcription/transactions) in preventing Cse4 mislocalization to euchromatin by mediating its proteolysis [58]. They initially found that Psh1 cannot efficiently ubiquitylate Cse4 nucleosomes in vitro, suggesting that additional factors must facilitate Cse4 removal from chromatin in vivo. The Spt16 subunit (Figure 1b and Table 1) of the FACT complex binds to Psh1, and this interaction between Psh1 and Spt16 is critical for both Cse4 ubiquitylation and its exclusion from euchromatin. Therefore, a Psh1 mutant that cannot associate with FACT has reduced interaction with Cse4 in vivo. Collectively, they proposed a previously unknown mechanism to maintain centromere identity and genomic stability through the FACT-mediated degradation of ectopically localized Cse4.
Hewawasam et al. reported that Psh1 is phosphorylated by the Cka2 subunit of casein kinase 2 (CK2) to promote its E3 activity for Cse4 [29] (Figure 1a and Table 1). They first showed that the deletion of
Mishra et al. showed that a kinetochore protein, Pat1 (Figure 1, right and Table 1), protects
One interesting question is if Cse4 misincorporation affects promotor function and transcriptional regulation. Hildebrand et al. addressed the genome-wide misincorporation pattern of Cse4 in the presence and absence of Psh1, performing chromatin immunoprecipitation analysis followed by high throughput sequencing [59]. They found that ectopic Cse4 mislocalized to intergenic regions of the genome. Mislocalized Cse4 is enriched at promoters that contain histone H2A. ZHtz1 nucleosomes flanking nucleosome-depleted regions (NDRs), however, Cse4 mislocalization does not depend on H2A.ZHtz1. Instead, the chromatin remodeling inositol-requiring 80 (INO80) complex (INO80-C), which removes H2A.ZHtz1 from nucleosomes, contributes to the ectopic deposition of Cse4 [59] (Figure 1, left). However, the functional relationship of INO80-C with other factors (e.g., CAF-1 complex) for Cse4 ectopic deposition remains to be elucidated (Figure 1, left). Together, this transcriptional profiling revealed that mislocalized Cse4 significantly disturbs transcription in the absence of Psh1, suggesting that regulating centromeric nucleosome localization is important for ensuring accurate promoter function and transcriptional regulation.
Because Cse4 proline residues though the Fpr3 regulation influence its degradation as reported by Ohkuni et al. [32] (see also Section 1.2.3), Deyter et al. hypothesized that additional features of the Cse4 nucleosome might be important for Cse4 proteolysis [31]. They initially asked whether histone H4 residues are important for Cse4 degradation, since Cse4 binds with high affinity to histone H4 before and after deposition on DNA, and they determined that Cse4 protein levels are stabilized in H4-R36A mutant cells and Cse4 is enriched in the euchromatin. Consistent with those data, they also demonstrated that H4-R36 is important for the interaction between Cse4 and Psh1 (Figure 1 and Table 1). They also analyzed Psh1 localization in WT vs. H4- R36A cells at the 5′, 3′, and coding regions of two highly transcribed genes,
This group previously had discovered that overexpressed Cse4 is mislocalized to nucleosomes in both tandem and divergent intergenic regions in the absence of Psh1, as shown earlier [59]. Therefore, they tested whether this is also true in the H4-R36A mutant cells by performing ChIP-qPCR. Cse4 mislocalization was negatively correlated with Psh1 enrichment in H4-R36A cells. Taken together, these data revealed H4-R36 is a key residue for efficient Cse4 degradation, likely by facilitating the interaction between Psh1 and Cse4.
Eisenstatt et al. further utilized a genome-wide screen (SGA) to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of the
One question is how this H4 dosage balance affects the function of H4-R36 (see also Section 1.5.1). Deyter et al. reported that H4-R36 is a key residue for efficient Cse4 degradation, likely by facilitating the interaction between Psh1 and Cse4 [31]. This group also found that a basic residue at H4-R36, but not PTM (e.g., methylation) of the amino acid, is required to prevent sensitivity to Cse4 overexpression [31]. Then how is it possible that reduced dosage of H4 leads to sumoylation and reduced mislocalization of overexpressed Cse4? Eisenstatt et al. showed that deletion of either histone H4 allele resulted in reduced levels of sumoylated Cse4 and concluded that physiologic levels of histone H4 are required for Cse4 sumoylation [27] (see also Section 1.4). However, the level of sumoylation loss caused by the deletion of either histone H4 allele (in
The mechanism by which other histones’ PTMs and dosages are involved in the incorporation of CENP-A/CenH3 is highly interesting, but at the same time, it suggests many questions. A further question raised is whether H4 dosage affects heterotypic CENP-A-H3.3 nucleosomes (see also Section 1.6) or H3 dosage among species including humans? Results in both budding and fission yeast suggest that the balance among histones H3,H4 and CENP-A is important for centromeric chromatin assembly [60, 61]. In fission yeast, increasing cellular histone H3 levels relative to Cnp1 promotes accumulation of H3 and loss of Cnp1 from the central domain and leads to defects in kinetochore function, however, there does not appear to be an efficient mechanism for the active exclusion of histone H3 from the centromeric nucleosomes [60, 62]. If H4 dosage affects heterotypic CENP-A-H3.3 nucleosomes or H3 dosage, is there an indirect pathway through which H4 dosage affects CENP-A incorporation into chromatin through H3? The inter-regulation among different histones, including CENP-A/CenH3 for high(macro) and low(micro) order chromatin structures, must be intricate. However, this could make it difficult to elucidate the mechanisms of incorporation, maintenance, and inheritance of CENP-A/CenH3.
In fission yeast and human studies, Mis18 (human Mis18α and Mis18β homolog) and Mis16 (human RbAp46 and RbAp48 homolog) are required for loading of newly synthesized Cnp1/CENP-A into centromeric chromatin [63, 64] (see also next chapter, sections 2.1, 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 [64], and Mis16 homologs are components of several histone chaperone complexes [65]. 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 [66], consistent with the Hat1 role shown in
It is known that sumoylation is involved in multiple intercellular pathways, and a subset of polysumoylation-mediated polyubiquitylation processes lead to proteasome-mediated degradation [70, 71]. Such machineries of SUMO-dependent ubiquitylation and degradation of CENP-A are interesting and important issues. Recent research has revealed new insights about the sumoylation of Cse4.
Ohkuni et al. reported the first evidence that Cse4 is sumoylated by E3 ligases Siz1 and Siz2 in vivo and in vitro [28] (Figure 1 and Table 1). Siz1 is the founding member of the Siz/PIAS (protein inhibitor of activated STAT) RING family of SUMO E3 ligases, and both Siz1 and Siz2 are normally bound to chromatin via their SAP domains [72]. The Siz/PIAS RING family is involved in the sumoylation of the septin protein group and several chromatin proteins including core histones and the replication clamp PCNA (proliferating cell nuclear antigen) [70, 72]. They showed that ubiquitylation of Cse4 by the small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligase (STUbL), Slx5, is important for proteolysis of Cse4 and prevents mislocalization of Cse4 to euchromatin under normal physiologic conditions (Figure 1b and Table 1). Sumoylated Cse4 proteins are accumulated and protein stability of Cse4 is increased in
Further, Ohkuni et al. identified lysine 65 (K65) in Cse4 as a site that regulates sumoylation and ubiquitin-mediated proteolysis of Cse4 through Slx5 [52] (Figure 1b). The abundance of sumoylated and ubiquitinated Cse4 in vivo is reduced in budding yeast strains expressing cse4 K65R. They also showed that the interaction of cse4 K65R with Slx5 is significantly reduced, and stability and mislocalization of cse4 K65R are increased under normal physiologic conditions. The stability of cse4 K65R in
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 (a member of a large family of Sentrin-specific protease enzymes that belongs to the yeast Ulp2 group) stabilizes CENP-I by antagonizing RNF4 [73]. However, 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 [73]. Recent analyses by some groups also indicated that CENP-A was not a direct substrate of SENP6 [74, 75]. Differences among species of roles of sumoylation in the regulation of CENP-A stability are described later (see also next chapter, section [4]).
C-terminal sumoylation of Cse4 also contributes to the deposition of Cse4 into chromatin. Ohkuni et al. identified sumoylation sites lysine (K) 215/216 in the C-terminus of Cse4 and showed that sumoylation of Cse4 K215/216 facilitates its genome-wide deposition into chromatin when overexpressed [21] (Figure 1). Their results showed reduced levels of sumoylation of mutant Cse4 K215/216R/A [K changed to arginine (R) or alanine (A)] and reduced interaction of mutant Cse4 K215/216R/A with Scm3 and CAF-1 (Figure 1 and Table 1) (see also Section 1.5.3) when compared to wild-type Cse4. Consistently, levels of Cse4 K215/216R/A in the chromatin fraction and localization to centromeric and noncentromeric regions were reduced. In addition, GAL-cse4 K215/216R does not exhibit synthetic dosage lethality (SDL) in these strains—unlike
Further questions remain about the SUMO E3 ligase of Cse4 C-terminal K215/216 sumoylation. Sumoylation of Cse4 is barely detectable in a
Samel et al. reported that the absence of the E3 ubiquitin ligase Ubr2, as well as its adaptor protein Mub1, suppresses the synthetic growth defects (or lethality) caused by the absence of Cse4-R37 methylation in
However, the relationship between Ubr2 and Psh1, and E3 activity of Ubr2 on Cse4 is still not clear, although the absence of both E3s suppressed the synthetic growth defects (or lethality) shown in their study. The authors stated that most likely increased levels of kinetochore proteins other than Dsn1 in
In addition to the aforementioned report of Slx5 by Ohkuni et al. [28], Cheng et al. demonstrated that 4 ubiquitin ligases (i.e., Ubr1, Slx5, Psh1, and Rcy1) (Figure 1c and Table 1) contribute in parallel to the Cse4 proteolysis and turnover in budding yeast cells [33]. Cse4 overexpression generates cellular toxicity and cell cycle delay in budding yeast cells lacking
On the other hand, Cheng et al. also noted the lack of clarity about how this different E3s collaborate [33]. Their finding also generated these questions:
How do these E3s specifically recognize Cse4?
How do they work with other cellular cues and pathways (e.g., casein kinase 2, Siz1- and Siz2-mediated sumoylation, SWI/SNF remodeling enzymes, the FACT complex, and the proline isomerase Fpr3)?
What is the functional role and mechanism of each degradation pathway?
Further study is required to address these intricate E3 networks of Cse4 as well as other kinetochore proteins. In addition, the ubiquitin ligase(s) involved in human CENP-A degradation still remains unclear, although the CUL4A complex was identified as an E3 ligase that is required for CENP-A deposition at the centromere [79] (see also next chapter, section [4.2]). As Cheng et al. noted, while Psh1 does not seem to have a mammalian counterpart, Ubr1 (human UBR1), Slx5 (human RNF4) and Rcy1 (human EXOC5) are known to have human homologs. It is highly interesting to test CENP-A turnover in mammalian cells deficient for these homologs and also to determine if the human homologs of these E3s are altered in CENP-A-related cancer cells. Analogous questions are also raised in Section 1.6.2.
Hewawasam et al. reported that chromatin assembly factor-1 (CAF-1) (Figure 1 and Table 1) controls Cse4 deposition in budding yeast (see also Section 1.4.2). CAF-1 is an evolutionarily conserved histone H3/H4 chaperone; its subunits were shown to interact with CenH3 in flies and human cells. Previously, it had been reported that subunits of CAF-1 are required for building functional kinetochores [80], for recruitment of CenH3/Cnp1 and Scm3 to centromeres in fission yeast,
Some questions remain about the relationships among Cse4, Psh1, Scm3, and CAF-1. The first question is about the role of CAF- 1 in Psh1-mediated proteolysis of Cse4: How does CAF-1 function in the process of Cse4 ubiquitylation by Psh1? Hewawasam et al. observed more ubiquitylation of Cse4 in the presence of CAF-1 compared with the absence of CAF-1 in vitro, suggesting CAF-1 can promote ubiquitylation of free Cse4, opposite to the effect of Scm3 that protects Cse4 from ubiquitylation by Psh1 in vitro [22]. They also tested CAF-1 interaction with Psh1, but their co-immunoprecipitation experiment in whole-cell extracts did not show any interactions. Thus, they speculated that soluble Cse4 bound to CAF-1 may expose ubiquitylation sites on Cse4, promoting ubiquitylation by Psh1.
The second question is whether CAF-1 could assemble Cse4 at centromere as Scm3. If so, do the roles of the two proteins simply overlap, or does each protein have a unique role in the process of Cse4 assembly at centromere? To test this question, Hewawasam et al. used the Scm3on/off strain, which can be toggled by galactose, along with copper-inducible Cse4 overexpression, so that Cse4 protein levels can be controlled by the concentration of copper [26]. Their results suggest that when Scm3 is absent and Cse4 levels are high, CAF1 may be a primary chaperone targeting Cse4 to the centromere (Figure 1, center). Meanwhile, in the fission yeast
The third question is how CAF-1 can be responsible for the mislocalization of Cse4/CENP-A in cancer development. The human CAF-1 subunit p60 was one of the overexpressed chaperones in CENP-A-overexpressing breast cancer cells [82], and ectopic CENP-A nucleosomes from colorectal cancer cells keep a subpopulation of structurally distinct hybrid (chimeric) nucleosomes containing both CENP-A and H3.3 [82, 83]. Misregulation of Scm3/HJURP causes chromosome instability in both yeast and humans [84], and many previous reports suggested the functional relevance of Scm3/HJURP with the development of a wide spectrum of cancers (e.g., colon, lung, liver, breast, pancreatic, brain cancer) [85, 86, 87, 88, 89, 90, 91, 92, 93, 94]. As aforementioned, CAF-1 may cooperate with Psh1 and Scm3 to regulate proteolysis of Cse4, in the way that CAF-1 association with free Cse4 may promote ubiquitylation and proteolysis. If so, how do these two chaperons (CAF-1 and Scm3/HJURP) cooperate together in genomic stability and anti-cancer development? Further in-depth study is required to elucidate the collaboration among Psh1, Scm3, and CAF-1 in genomic stability and anti-cancer development.
Deletion for genes encoding the replication-independent histone chaperone HIR complex (HIR1, HIR2, HIR3, HPC2) and a Cse4-specific E3 ubiquitin ligase, PSH1, showed the highest SDL using a genome-wide synthetic genetic array (SGA) to identify gene deletions that exhibit SDL when Cse4 is overexpressed [30]. Thus, Ciftci-Yilmaz et al. performed functional analysis for Hir2 (Figure 1 and Table 1) in proteolysis of Cse4 that prevents mislocalization of Cse4 to noncentromeric regions for genome stability. They demonstrated the interaction of Hir2 with Cse4 in vivo, and defects in Cse4 proteolysis and stabilization of chromatin-bound Cse4 appear in
Analogous questions can be raised regarding CAF-1, especially about the functional relationships among different Cse4 chaperone proteins (e.g., Scm3, CAF-1, and Hir2) and their roles in cancer development. In the Psh1-mediated proteolysis of free Cse4 using whole-cell lysates, CAF-1 and Hir2 promote proteolysis and Scm3 inhibits it [22, 26, 30]. CAF-1 and Hir2 could be involved in the proteolysis of noncentromeric Cse4, but Scm3 in the anti-proteolysis of the centromeric Cse4. However, CAF-1 may promote centromeric localization of overexpressed Cse4 only under conditions when Scm3 is depleted (
Studying the real-time 3D structure of free CENP-A/CenH3 after post-translational modification and before incorporation into chromatin could be a key future direction. In budding yeast, Ohkuni et al. proposed that structural change in Cse4 caused by the proline isomerase Fpr3 might be important for the interaction between Cse4 and the E3 ubiquitin ligase Psh1 [32] (see also Section 1.2.3).
Au et al. identified two Skp1, Cullin, F-box (SCF) ubiquitin ligases with the evolutionarily conserved F-box proteins Met30 and Cdc4 (Figure 1c and Table 1) as essential genes required for Cse4 homeostasis through a genome-wide SGA screen [34]. They showed that Met30 and Cdc4 interact through the Met30-WD40 domain, and these two proteins cooperatively regulate proteolysis of endogenous Cse4 and prevent its mislocalization for faithful chromosome segregation (Figure 1). The interaction of Met30 with Cdc4 is independent of the Met30-D domain, which is essential for their homodimerization and ubiquitination of other substrates. Ubiquitin affinity pull-down assays showed that both Cdc4 and Met30 specifically target Cse4 for its ubiquitination. They suggest that Met30 is necessary for the interaction between Cdc4 and Cse4, and its defective interaction leads to stabilization and mislocalization of Cse4, which in turn promotes to CIN. They also provided the first direct link between Cse4 mislocalization and defects in kinetochore structure measured by the sensitivity against the restriction enzyme
Further studies are also required to address analogous questions as in Section 1.5.2: How does the Met30/Cdc4-pathway work with other cellular cues and multiple E3 pathways, including Psh1-dependent and independent proteolysis? Are the human homologs of these E3s (e.g., human FBXO24, TRAF7, etc.) altered in CENP-A-related cancer cells?
Eisenstatt et al. identified five alleles of CDC7 and DBF4 that encode the Dbf4-dependent kinase complex, which regulates DNA replication initiation in their SGA [95]. They found that cdc7–7 strains show defects in ubiquitin-mediated proteolysis of Cse4 and mislocalization of Cse4 [95]. Mutation of MCM5 (mcm5-bob1) bypasses the requirement of Cdc7 for replication initiation and rescues replication defects in a cdc7-7 strain. They demonstrated that mcm5-bob1 does not rescue the SDL and defects in proteolysis of overexpressed Cse4 (
Recently, Eisenstatt et al. further utilized SGA to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of the
Compared to the ubiquitylation mechanism of Cse4, there are relatively few studies on the deubiquitylation mechanism of Cse4. We should also consider how the deubiquitylation affects the localization and the function of Cse4 at both centromere and ectopic sites along chromosomes.
Canzonetta et al. investigated the role of Ubp8-driven deubiquitylation of the Cse4 in budding yeast [96]. Ubp8 is a component of the SAGA (Spt-Ada-Gcn5-acetyltransferase) complex, a multicomponent regulator of acetylation. The SAGA complex is also involved in deubiquitylation through its deubiquitylation (DUB) module, and one example of its activity is upon histone H2B [97, 98]. Canzonetta et al. demonstrated that the deubiquitylation process was inhibited and a short ubiquitin oligomer on Cse4 was accumulated by the loss of Ubp8. Such defective deubiquitylation caused by Ubp8 loss leads to chromosome instability and Cse4 protein degradation, and induces ectopic localization of the Cse4 outside the centromere.
Interestingly, there was a report suggesting that Psh1 is also involved in proper plasmid segregation [99]. Metzger et al. initially sought to assess the involvement of the ubiquitin-proteasome system in the turnover of mitochondrial proteins in budding yeast [99]. Then, they found that deletion of a specific ubiquitin ligase (E3), Psh1p, increases the level of a temperature-sensitive mitochondrial protein, mia40-4pHA, when it is expressed from a centromere-containing (
Zhou et al. first solved the structure of the Cse4-binding domain (CBD) of Scm3 in complex with Cse4 and H4 in a single chain model using nuclear magnetic spectroscopy [12]. They suggested that four Cse4-specific residues in the N-terminal region of helix 2 (MIMAS motif; Table 1) are sufficient for specific recognition by conserved and functionally important residues in the N-terminal helix of Scm3 through the formation of a hydrophobic cluster.
Scm3 (CBD) also induces major conformational changes and sterically occludes DNA-binding sites in the structure of Cse4 and H4. Furthermore, Zhou et al. showed that Psh1 uses a CBD (residues 1–211) to interact with Cse4-H4 instead of H3-H4, yielding a dissociation constant (Kd) of 27 nM in their isothermal titration calorimetric experiments [100]. They are in vitro pull-down assays revealed that Psh1 interacts with Cse4-specific residues in the L1 loop and α2 helix for Cse4 binding and ubiquitination. They also mapped the Psh1-binding region of Cse4-H4 and identified a wide range of Cse4 specific residues required for the Psh1-mediated Cse4 recognition and ubiquitination. Consistent with the previous reports of the inhibitory effect of Scm3 on Cse4 ubiquitylation [22], their data showed that the histone chaperone Scm3 prevents Cse4 ubiquitination by abrogating Psh1-Cse4 binding. Their results suggest that Scm3 interacts with the Cse4 MMAS motif (a particular Cse4 region containing residues M181/M184/ A189/S190 reported previously [12]) to prevent Psh1 from binding to Cse4. Elimination of the Psh1-binding residues outside of the Cse4 MMAS motif promotes the inhibitory effect of Scm3. Thus, the MMAS motif plays a central role in the activation or inhibition of Cse4 ubiquitination as well as yeast cell growth. Taken together, they elucidated a novel Cse4 binding mode distinct from those of known CenH3 chaperones and the mechanism by which Scm3 competes with Psh1 for Cse4 binding.
The budding yeast is a powerful organism for centromere-kinetochore research in many aspects. 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 [1]. 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. As a result, the most common species studied and reported in the past for E3 ligase of CenH3 (Cse4) is budding yeast at present. However, many questions described in this chapter are unanswered even in the budding yeast model. Especially, little has been studied on how each of such multiple E3 ligases of budding yeast selectively recognizes Cse4 substrate and functions specifically. Currently, 4 types of E3 ligases for ubiquitylation and one type of E3 ligases for sumoylation (Slx5/8) have been reported (Table 1). In particular, the functions of the 4 types of E3 ligases for ubiquitylation including Psh1 are common, all of which are related to ectopic degradation and/or quality control of soluble or chromatin-bound Cse4, and the functional differences are not clear. It is neither clear why E3 ligases with overlapping functions exist in one species. The simple interpretation is that at least such a number (4–5) of E3 ligases of Cse4 is required as a backup system, so that it can be complemented if one of the E3 functions is defective. As we described the compensatory system of CENP- A PTM (see also the next chapter, Conclusion), compensatory systems and resilience of CENP-ACse4 could be expected as future directions to study the spatiotemporal regulation of E3 ligase of CENP-ACse4.
No neocentromere has been found in budding yeast. As a simple reason, it seems that there is no or little possibility of ectopic centromere formation, because the kinetochore formation of budding yeast depends on centromeric DNA elements. However, in terms of considering centromeric evolution, it is interesting to question why budding yeast has maintained point centromere which relies on DNA elements, and other species have evolved to regional centromere which allows the system to generate neocentromere? There is also no clear answer as to whether simply introducing centromeric DNA elements into ectopic loci causes neocentromere or it is still eliminated by the specific E3 activity in budding yeast. The building and establishment of artificial chromosomes are facilitated by studying the mechanisms of formation and maintenance of neocentromeres, and these topics of other species are described in the next chapter.
The regulation of budding yeast cenRNA is an essential factor for centromere structure and function as other eukaryotes, but we have little understanding of the causality or feedback between cenRNA transcription and overall transcriptional change after chromosome mis-segregation and CIN. In addition, little is known about 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, it is essential to study specific physiological functions of each E3 ligase, the physiological phenotype of budding yeast is limited (e.g., growth, cell death, etc.), thus naturally there is a limit in the discussion of the results in the budding yeast model. Thus, studies of an E3 ligase in CENP-A in higher eukaryotes, mammals, or humans are essential for translational research and informing future therapy, and these topics are described in the next chapter.
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.
The authors declare no conflict of interest.
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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. 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