Open access peer-reviewed chapter

The Role of Deubiquitinases in DNA Double-Strand Break Repair

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Jun Lu, Zhi-Feng Xi, Xiao-Ying Huang, Qiang Xia and Xi-Dai Long

Submitted: December 20th, 2016 Reviewed: December 21st, 2017 Published: January 26th, 2018

DOI: 10.5772/intechopen.73341

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DNA double-strand break (DSB) is a type of the most critical DNA lesions, and if not repaired promptly, it can result in cell death or a wide variety of genetic alterations including genome instability, large- or small-scale deletions, chromosome loss, loss of heterozygosity, and translocations. DSBs are repaired by double-strand break repair (DSBR), including nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathway, and defects in these pathways cause genome instability and promote tumorigenesis. Accumulating evidence has demonstrated that the superfamily of deubiquitinases (DUBs) can regulate the action and stability of DNA repair enzymes involving in DSBR via modifying ubiquitination levels, a reversible posttranslational modification pathway. In this review, we will discuss ubiquitination/deubiquitination modification involving in DSBR genes, the role of DUBs in DSBR and corresponding mechanisms, and the potential effects of this modification on human diseases.


  • double-strand break repair
  • deubiquitinase
  • ubiquitination
  • deubiquitination
  • double-strand break

1. Introduction

DNA double-strand break (DSB) is a fatal alteration in the chemical structure of DNA; if it has not been repaired in time, it may destroy the stability of genome and lead to a series of human diseases. Usually, they result from a variety of causes including abnormal metabolic process, ionizing radiation, ultraviolet radiation, and active oxygen damage factors [1, 2]. In organism, DNA double-strand break repair (DSBR), a complex reaction system consisting of nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathway, can repair DSBs [3, 4]. Accumulating evidence has demonstrated that ubiquitination and deubiquitination modification play a vital role in controlling the capacity of DSBR via regulating the action and stability of DNA repair enzymes involving in DSBR pathway. In the past decades, there has been great advance in the role of deubiquitinases (DUBs) in DNA damage repair. Here, we reviewed ubiquitination/deubiquitination modification of DSBR genes, the role of DUBs in DSBR and corresponding mechanisms, and the potential effects of this modification on human diseases.


2. Ubiquitination and deubiquitination

Ubiquitin is an important single-chain polypeptide consisting of 76 amino acid residues and ubiquitously exists in almost all eukaryotic cells and tissues [5, 6]. This polypeptide is characterized by highly conserved protein from yeast to human [6] and is invariant in higher plants and differs by only three residues from animals [7]. Structurally, ubiquitin polypeptide chain appears to be a highly compact β-grasp fold with an α-helix in the cavity formed by a five-strand mixed β-sheet and a marked hydrophobic core formed between the β-sheet and the α-helix [8]. A flexible six-residue tail in the C-terminal of ubiquitin protrudes from β-grasp fold and is requested for forming the bond between ubiquitin and its substrate [9].

Ubiquitination is defined as the process that ubiquitin attaches to its target proteins via catalysis of enzymes. This process is a reversible posttranslational modification that can regulate various processes including cell proliferation, apoptosis, transcription, protein stability and translocation, and DNA damage repair [10, 11, 12]. Ubiquitination process is an ATP-dependent enzymatic cascade reaction [13, 14]. During cascades reaction, C-terminal of ubiquitin is first adenylated by ubiquitin-activating enzyme (E1) via forming a bond between the adenosine monophosphate (AMP) and the C-terminal glycine carboxyl group of ubiquitin, and subsequently, the E1 cysteine side chain directly binds to C-terminal and results in the formation of a thiol-ester linkage. Then, the activated ubiquitin is presented to the active cysteine in a ubiquitin-conjugating enzyme (E2). The E2 delivers the ubiquitin to its substrate cooperating with ubiquitin ligases (E3), which plays a role in substrate recognition. Finally, the C-terminal glycine of the ubiquitin binds to a lysine residue of the substrate with an isopeptide bond. After multiple cycles of cascade reaction, substrate will bind one or more polyubiquitin chains that are formed between the lysine side of one ubiquitin and the C-terminal carboxyl group of another ubiquitin [13, 14]. The 26S proteasome can specifically recognize these target proteins with ubiquitination modification and lead them into ubiquitin-proteasome pathway (UPP) for inducting protein degradation, a key role of ubiquitination. However, UPP is not the only role of ubiquitination. Ubiquitination can also regulate protein activity and the interaction among proteins [13, 14].

Deubiquitination is the reverse process of ubiquitination and regulated by deubiquitinases (DUBs). DUBs, also known as deubiquitinating enzymes, can cleave the bonds between substrate and polyubiquitin chains and improve the stability of substrate. They can also remove single ubiquitin molecule from polyubiquitin chains. Until now, approximately 561 DUBs have been identified in the human genome [15], and most of them are cysteine proteases. According to the difference in their structure and function, DUBs are divided into six classes: ubiquitin-specific proteases (USPs), ubiquitin carboxy-terminal hydrolases (UCHs), ovarian tumor proteases (OTUs), Machado-Joseph disease protein domain proteases (MJDs), JAMM/MPN domain-associated metallopeptidases (JAMMs), and the monocyte chemotactic protein-induced protein (MCPIP) family. These enzymes can stabilize protein and play a crucial role in the life process [13, 14].


3. DSBs and DSBR pathways

3.1. DSBs and DSB response

DSBs are vital DNA damages caused by a variety of physiological or pathological factors. V(D)J recombination has been identified as the only physiological reason inducing DSBs that result from the recombination of variable (V), diversity (D), and joining (J) gene segments. It often appears in the early development process of the vertebrate immune system. Evidence has shown that diverse immunoglobulins and T-cell receptors are generated due to this special recombination pathway. During V(D)J recombination, DNA strands are cut by RAG-1 and RAG-2 protein between the recombination signal sequences (RSS) heptamer and the flanking sequence and result in the formation of DSBs [16, 17], whereas the ends of the broken strands are subsequently processed and connected through NHEJ pathway [18].

For pathological factors, reactive oxygen species (ROSs) resulting from cellular oxidation are one main source of pathological DSBs. Studies have shown that about one percent of the oxygen that we breathe is converted into oxidative free radicals and ultimately can cause DSBs in different degrees [19]. Pathological DSBs can also arise from DNA replication across a nick that is caused by exogenous or endogenous sources. Such ionizing radiation as X-rays and gamma rays may produce free radicals and induce the formation of DSBs [20]. This type of DSBs only occurs in the S phase and is repaired through HR pathway. Additionally, one unusual cause producing DSBs is the topoisomerase II poisons that can lead to DSBs formation, apoptotic cell death, and genomic instability via stabilizing the DNA topoisomerase II cleavable complexes [21]. Another unusual cause is physical stress on the DNA duplex, which may be from the mitotic spindle on chromosomal fusions or telomere failures [22].

Studies have shown that DSBs can induce DNA damage response, and such E3 ligases as ring finger protein (RNF8) subsequently accumulate around the lesions. After that, RNF8-recruiting RNF168 promotes histone H2A Lys13,15 mono-ubiquitination (H2AK13, 15ub). Therefore, the accumulation of DNA-repair regular factors, such as receptor-association protein (RAP80) and TP53 binding protein (53BP1), is allowed [23, 24, 25, 26]. Finally, the ataxia telangiectasia mutated (ATM) and ATM/rad3-related (ATR) kinases, a central regulator of DSB response, are activated and induce the activation of Chk1 and Chk2 kinases and TP53 protein. The activated Chk1 and Chk2 kinases arrest cell cycle to obtain sufficient time for DNA repair, while activate TP53 induces cell death [27, 28].

3.2. DSBR pathways

Merely one DSB that triggers apoptosis or destroys a critical gene is enough to lead a cell to death [29], whereas losing ability to repair DSBs can also lead to genome rearrangement and cellular transformation [30]. In organism, the two primary pathways to correct DSBs are known as HR pathway and NHEJ pathway. For NHEJ pathway, it can repair DSBs with nonhomological damaged ends and is the primary DSBR pathway in mammalian cells. This pathway consists of classical-NHEJ (C-NHEJ) and alternative-NHEJ (A-NHEJ). In C-NHEJ, Ku heterodimer (Ku70 and Ku80 subunits) recognizes and binds to the ends of a DSB to prevent the free ends from degradation. Subsequently, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is recruited and then binds to Ku heterodimer to recruit XRCC4 and DNA ligase 4 (LIG4). XRCC4 and LIG4 form a complex with XLF to ligate the broken ends [31, 32]. Until now, although the detailed mechanism of NHEJ is poorly understood, a recent study has partly revealed the mechanism about how the complex of XRCC4, LIG4, and XLF connects the fragments of broken DNA [33]. It has shown that XRCC4-XLF complex first bridges the two DNA molecules generated by DSBs, and the bridge can slide along the DNA. Then, the ends of broken DNA are rapidly reconnected. Evidence from molecular epidemiological and genetical studies displays that low or losing capacity of NEEJ pathway is positively associated with the deficiency of immune reaction [34, 35]. For example, about 15% of human severe combined immune deficiency (SCID) has been observed to feature low NHEJ capacity caused by null mutations of Artemis gene [34, 35]. Patients carrying the mutations in the DNA ligase IV gene that is crucial in NHEJ pathway presented some NBS-like features; however, cancers were not observed on these patients [36].

For HR pathway, it was first illuminated in Escherichia coli and Saccharomyces cerevisiae [37], and the similar mechanisms of the key reaction in HR pathway are observed in bacteria, yeast and human cells. An intact double-strand DNA that has highly homologous sequence of the damaged molecule is needed to act as the template to direct repair [38]. HR pathway includes three main steps: termini procession, strand invasion and branch migration, and Holliday junction formation. The ends of DSB are first processed by a nuclease, such as Mre11-Rad50-NBS1 (MRN) complex, and produce a single-stranded region with a 3′ overhang. Replication protein A (RPA) subsequently binds to the single-strand region for stabilizing and protecting this single-strand status [39, 40]. The core procedure of HR pathway is RAD51-depended strand invasion and branch migration. RAD51 displaces the RPA from single-strand DNA to form a nucleoprotein filament and then directs the later to recognize homologous duplex DNA [41]. DNA strand exchange generates a Holliday junction between the homologous damaged and undamaged DNAs under the condition of cooperating RAD51 with RAD52, RAD54, and RAD55/57 protein. Finally, the MUS81/MMS4 can resolve Holliday junction to stop the process of HR pathway [3].

Except for above-mentioned directly regulated proteins, DSB response factors (including ATM/ATR and BRCA1/BRCA2) can indirectly regulate the capacity of HR pathway [42, 43, 44, 45, 46]. The defects of ATM may alter kinetics of radiation-induced RAD51 formation and the hallmark of RAD51 activation [42]. ATM/ATR can also mediate the phosphorylation of PALB2 to promote the formation of RAD51 nucleofilaments [43]. However, roles of ATM and ATR in HR pathway are still poorly understood. BRCA1 is a protein with 1863 amine acids encoded by breast cancer susceptibility gene and can target DSB lesion through its N-terminal RING domain binding to BRCA1-associated RING domain 1 (BARD1) [44]. BRCA1 can also promote HR pathway via cooperating with RAD51 and forming the complex of BRCA1-PALB2-BRCA2-RAD51 (BRCC) [44]. Surprisingly, BRCA1 can also prevent HR pathway by its incorporating into the complex of BRCA1-Abraxas-RAP80-MERIT40 (BRCA1-A). This may be because BRCA1-A can limit DNA end-resection or sequester BRCA1 away from HR sites by binding to RNF8/RNF168-ubiquitylated chromatin [45, 46]. Studies have shown that low or lost capacity of HR pathway resulting from these causes may cause a series of cancer-prone diseases, including ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome, Werner syndrome, and Fanconi anemia, reviewed by Thompson and Schild [47].


4. Deubiquitinases regulating DSBR

4.1. USPs

USPs, the largest subfamily of DUBs with approximately 100 members and the most divers structures, belong to cysteine protease family (clan CA, family C19) and were first identified in Saccharomyces cerevisiae [48]. The size of USPs is ranging between 330 and 3500 amino acids, with 800 and 1000 residues. These DUBs have three functional domains: a catalytic domain, a protein-protein interaction domain, and localization domain [48]. In the catalytic domain, USPs are marked with two short and well-conserved sequences, also called as the N-terminal Cys-box and the C-terminal His-box. These sequences are essential for catalytic activity of USPs [48, 49], while other domains provide the information of binding to their target protein. Interestingly, almost all the UBP deubiquitinases display a conserved three-domain architecture, comprising Fingers, Palm, and Thumb, and their C terminus are settled in the active site between the Palm and the Thumb, except for CYLD that has an obviously truncated Fingers subdomain [50, 51]. A later study has shown that the core catalytic domain of USPs contains six conserved boxes, and that boxes 1 and 2, boxes 3 and 4, and boxes 5 and 6 formed Thumb subdomain, Fingers subdomain, and Palm subdomain, respectively [52]. USPs have been found to involve in many diseases, such as cancer, inflammation and viral diseases [53]. At least 15 of USPs, including USP1, USP3, USP4, USP6, USP7, USP10, USP11, USP15, USP20, USP26, USP29, USP37, USP42, USP44, and USP51, can regulate DSBR.

USP1 contains 785 amino acids, and its catalytic domain is one of the largest among all USPs. Although two insertions between boxes 2 and 3 and between boxes 5 and 6 have been identified to locate away from the ubiquitin binding site of USP1, it is still not clear whether these insertions can reach the active site [52]. As USP1 has been reported to overexpress in osteosarcoma and non–small cell lung cancer, inhibitors of USP1 are supposed to have anti-cancer potential [54, 55]. Interestingly, USP1 can be stabilized by USP1-associated factor 1 (UAF1) that can increase the catalytic activity of USP1 [56]. This indicates that USP1 need to form a complex with UAF1 to carry out its functions. A recent study has further proved that three cell clones, USP1−/−, UAF1−/−/−, and USP1−/− UAF1−/−/− double-knockout cells, showed hypersensitivity to both camptothecin and poly (ADP-ribose) polymerase (PARP), suggesting that the USP1/UAF1 complex can promote HR capacity. Moreover, the USP1/UAF1 complex promoting HR capacity is at least in part associated with the suppression of NHEJ, although corresponding mechanisms still need to be further researched [57].

USP3 is a nuclear protein that presents in the chromatin fraction and is also a chromatin-associated DUB [58]. In 1999, Sloper-Mold et al. firstly identified and analyzed USP3 and found that a human USP3 gene probe detected two different mRNA transcripts that were expressed at low levels in all examined tissues [59]. USP3 is required for the deubiquitination of H2A and H2B to revert corresponding mono-ubiquitination. It has been displayed that USP3 can also regulate the cellular levels of ubiquitinated H2A and H2B (uH2A and uH2B), as H2A and H2B are the two major mono-ubiquitinated chromosomal protein [13, 58]. In addition, uH2A and uH2B have been revealed to associate with transcriptional regulation, where USP3 potentially plays a vital role [14]. Furthermore, the results from a study on mice with the deficiency of USP3 have shown that these mice can develop tumor spontaneously, and cells with the deficiency of USP3 fail to preserve chromosomal integrity [60]. For DSBR pathway, USP3 plays a key role in regulate DSB response. Transient USP3 silencing will cause spontaneous DNA damage, and DNA damage response will be enhanced at the same time [60]. The ubiquitination of histone H2A and γH2AX initiated by RNF168 and RNF8 in DSB response generates a cascade reaction and results in the accumulation of DSBR enzymes, whereas USP3 can oppose RNF168 and RNF8 via deubiquitination modification for the ubiquitinated H2A and γH2AX. Moreover, ectopic expression of USP3 can also block the accumulation of downstream repair enzymes such as BRCA1 and 53BP1 [61].

Except for USP3, several other USPs (including USP6, USP51, USP29, and USP44) can also deubiquitinate H2A [26, 62, 63]. Among these USPs, USP51 acts as a DUB for histone H2B mono-ubiquitination (H2Bub1), and the depletion of USP51 will suppress DSB reaction and tumor growth [64].

USP4, also named as ubiquitous nuclear protein (UNP), was initially found to promote carcinogenesis of lung and act as an oncogene [65, 66]. The following studies showed that USP4 is overexpressed in several types of human cancers such as hepatocellular carcinoma and plays a crucial role in the progression of tumorigenesis [67, 68]. Growing evidence has exhibited that USP4 affecting tumorigenesis may be correlated with abnormal DSBR capacity [67]. During DSBR pathway, USP4 may display its regulation functions on DSBR in several different processes, including DSB response and HR capacity. It has been identified to act as an important TP53 regulator that can decrease TP53 by deubiquitinating and stabilizing ARF-BP1, a ubiquitin ligase for p53 degradation [67]. During HR pathway, USP4 is required for CtIP recruitment to DNA damage site. It also regulates the resection of DNA DSBs via interacting with CtIP and the MRE11-RAD50-NBS1 (MRN) complex. The depletion of USP4 may abolish DNA end resection [69]. In addition, USP4 is ubiquitinated on multiple sites, and auto-deubiquitination of USP4 can promote CtIP recruitment and affect HR capacity [70].

USP11 and USP15 are two paralogs of USP4, and all of them share a common functional domain consisting of two ubiquitin-like (UBL) and a motif with ubiquitin-specific protease (DUSP) activity [71, 72]. USP11 is identified as a component of HR pathway, but the molecular mechanism is not clear [73], while USP15 is a DUB for murine double minute-2 (Mdm2), one of the E3 ligases that play a major role in regulating TP53 [74]. Thus, cell apoptosis induced by TP53 in DSB response may be inhibited by USP15 via deubiquitinating and stabilizing Mdm2. Except for USP15, USP26 can also deubiquitinate Mdm2 and play the same role as USP15 regulating TP53 [75]. Furthermore, USP26 and USP37 have been shown to inhibit the formation of BRCA1-A and promote the formation of BRCC. This function may involve in HR pathway [76]. However, further studies are needed to elucidate how USP26 and USP37 regulate HR pathway.

USP7, also called herpesvirus-associated ubiquitin-specific protease (HAUSP), is identified to act as a factor that promotes viral lytic growth, because it is associated with a herpesvirus protein ICP0 that is crucial for the viral lytic cycle [77, 78]. Substrates of USP7 are widespread, and a large part of them are tumor suppressors or oncogenes, such as TP53, PTEN, Chk1, Mdm2, and FOXO [79]. USP7 can regulate these tumor suppressors and play a key role in DSB response [80, 81, 82]. For example, USP7 directly deubiquitinates Chk1 in vivo and in vitro [83]; however, its family brother USP20 can only indirectly enhance the activity of ATR-Chk1 signaling by deubiquitinating Claspin [80]. Interestingly, deubiquitination of TP53 by USP7 prevents TP53 from degradation, whereas deubiquitination of Mdm2 by USP7 increases ubiquitination of TP53 and promotes the degradation of TP53 [81, 82]. This implies that the regulation of TP53 by USP7 is very complicated. Although USP7 displays its deubiquitination potential for both TP53 and Mdm2 that are substrates each other, this regulation potential is affected by different modificative status [81, 82]. Studies have shown that TP53 and Mdm2 bind to the same domain of USP7, but the binding capacity of Mdm2 is stronger except for phosphorylated status of Mdm2 induced by DNA damages [81, 82]. Additionally, USP10, USP29, and USP42 can deubiquitinate TP53, as well as USP7 [84, 85, 86]. However, they do not have the ability of deubiquitinating Mdm2. Thus, different USPs may exhibit different regulative potential for DSBR pathway via affecting different DNA repair factors such as Chk1, TP53, Mdm2, and so on [80, 81, 82] (Table 1).

USP1UnclearPromote HR and partly suppress NHEJ[57]
USP3H2A, γH2AXSuppress DNA DSB response[61]
USP4ARF-BP1, USP4Suppress p53-dependent apoptosis in DSB response[67, 70]
USP6H2ASuppress DNA DSB response[26]
USP7Chk1, p53, Mdm2Promote p53-dependent apoptosis in DSB response[81, 82, 83]
USP10p53Promote p53-dependent apoptosis in DSB response[84]
USP11unclearPromote HR[73]
USP15Mdm2Suppress p53-dependent apoptosis in DSB response[74]
USP20ClaspinPromote DNA DSB response[80]
USP26Mdm2Suppress p53-dependent apoptosis in DSB response and promote HR[75, 76]
USP29H2A, p53Suppress DNA DSB response and promote p53-dependent apoptosis in DSB response[63, 85]
USP37UnclearPromote HR[76]
USP42p53Promote p53-dependent apoptosis in DSB response or promote DSB response[86]
USP44H2ASuppress DNA DSB response[63]
USP51H2A, H2BSuppress DNA DSB response[62, 64]
OTUB1p53Promote p53-dependent apoptosis in DSB response not via its catalytic ability[87, 88]
OTUD5p53Promote p53-dependent apoptosis in DSB response[89]
POH1K63Promote HR but not via deubiquitinating K63[90]

Table 1.

DUBs regulate DNA DSBR.

4.2. OTUs

OTUs are divided into three subclasses: Otubians, A20-like OTUs, and other OTUs [91]. Otubians consist of OTUB 1 and OTUB 2 that are the first two proteins identified to display the DUB activity in vitro [92]. Structurally, OTUs are partly similar to USPs, exception for the incomplete catalytic triad [93, 94]. OTUs functionally involve in the regulation of diverse progresses, such as virus-triggered interferon induction, T cell anergy, and deubiquitination of p53 [87, 95, 96]. Interestingly, OTUB1 is a Lys48-specific DUB that can cleave ubiquitin from branched-polyubiquitin chains but not from ubiquitinated substrates. This DUB can bind to UBC13 (a cognate E2 enzyme for RNF168) and enhance DSB response potential via suppressing RNF168-dependent polyubiquitination but not via its catalytic ability [88]. OTUB1 also has the potential for directly deubiquitinating and stabilizing TP53 protein, which results in the decrease of cell death because of the increasing TP53 function [87]. Moreover, p53 is also the substrate of another OTU, OUTD5 [89]. OUTD5 has been shown to cleave the polyubiquitin chain from an essential type I interferon adaptor protein TRAF3 to interrupt the type I interferon signaling cascade [97]. As a DUB for p53, it can form a direct complex with p53 and is required for the p53-dependent apoptosis in response to DSB. Recently, increasing evidence has exhibited that the dysregulation of this DUB may involve in the development of several types of cancer, such as lung, colorectal, and colon cancer [98, 99, 100]. Taken together, the regulation of OTUs may result in the defects of DSBR and ultimately promote damaged-cell carcinogenesis.

4.3. JAMM/MPN domain-associated metallopeptidases (JAMMs)

JAMMs, the important members of metalloproteinase (MMP), contain JAMM/MPN domain-associated metallopeptidases sequences. These sequences include three conserved residues (two His and one Asp) that make up of catalytic center with two zinc ions [101]. The 26S proteasome-associated PAD1 homolog 1 (POH1) is a representative member of JAMMs and plays a key role in DSBR pathway. POH1 has been shown to be required for HR, which was supposed to associate with its ability to restrict 53BP1 through cleaving ubiquitin from the polyubiquitin chains of K63 protein. However, the result from another study showed that POH1-regulating HR process was independent of 53BP1 [90]. Thus, further studies are needed to elucidate detailed regulative mechanisms.


5. Summary and future directions

DSBR is a crucial DNA repair pathway and requests a series of DNA repair enzymes, whose activation is usually controlled via the post-translational modification regulation. In the regulation of DSBR capacity, DUBs play a vital role via deubiquitinating key proteins involving in DSBR pathway and/or enhance DSB response. However, there are several issues to be noted. First, although DUBs are a large posttranslational modification factor, only small part of them have functionally been identified. Second, despite DUBs that regulate DSBR capacity via increasing the stability and activation of DSBR enzymes, the detailed mechanisms are still unclear. Finally, some other signal pathways may affect DSBR, and it is not clear whether DUBs regulate these signal pathways. Thus, further studies are needed to solve more detailed molecular mechanisms of DUBs regulating DSBR.

Source of funding

This study was supported in part by the National Natural Science Foundation of China (Nos. 81760502, 81572353, 81372639, 81472243, 81660495, and 81460423), the Innovation Program of Guangxi Municipal Education Department (Nos. 201204LX674 and 201204LX324), Innovation Program of Guangxi Health Department (No. Z2013781), the Natural Science Foundation of Guangxi (Nos. 2017GXNSFGA198002, 2017GXNSFAA198002, 2016GXNSFDA380003, 2015GXNSFAA139223, 2013GXNSFAA019251, 2014GXNSFDA118021, and 2014GXNSFAA118144), Research Program of Guangxi “Zhouyue Scholar” (No. 2017-38), Research Program of Guangxi Specially-invited Expert (No. 2017-6th), Research Program of Guangxi Clinic Research Center of Hepatobiliary Diseases (No. AD17129025), and Open Research Program from Molecular Immunity Study Room Involving in Acute & Severe Diseases in Guangxi Colleges and Universities (Nos. kfkt20160062 and kfkt20160063).



AMPadenosine monophosphate
DSBDNA double-strand break
DSBRdouble-strand break repair
HRhomologous recombination
MCPIPthe monocyte chemotactic protein-induced protein
MJDMachado-Joseph disease protein domain protease
NHEJnon-homologous end-joining
OUTovarian tumor protease
ROSreactive oxygen species
RSSrecombination signal sequence
UCHubiquitin carboxy-terminal hydrolase
UPPubiquitin-proteasome pathway
USPubiquitin-specific protease


  1. 1. Ciccia A, Elledge SJ. The DNA damage response: Making it safe to play with knives. Molecular Cell. 2010;40:179-204. DOI: 10.1016/j.molcel.2010.09.019
  2. 2. Lagerwerf S, Vrouwe MG, Overmeer RM, Fousteri MI, Mullenders LH. DNA damage response and transcription. DNA Repair (Amst). 2011;10:743-750. DOI: 10.1016/j.dnarep.2011.04.024
  3. 3. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual Review of Biochemistry. 2004;73:39-85. DOI: 10.1146/annurev.biochem.73.011303.073723
  4. 4. O’Driscoll M, Jeggo PA. The role of double-strand break repair - insights from human genetics. Nature Reviews. Genetics. 2006;7:45-54. DOI: 10.1038/nrg1746
  5. 5. Goldstein G, Scheid M, Hammerling U, Schlesinger DH, Niall HD, Boyse EA. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proceedings of the National Academy of Sciences of the United States of America. 1975;72:11-15. DOI: 10.8424/PMID.1078892
  6. 6. Wilkinson KD, Audhya TK. Stimulation of ATP-dependent proteolysis requires ubiquitin with the COOH-terminal sequence Arg-Gly-Gly. The Journal of Biological Chemistry. 1981;256:9235-9241. DOI: 10.9258/PMID.6267067
  7. 7. Callis J, Carpenter T, Sun CW, Vierstra RD. Structure and evolution of genes encoding polyubiquitin and ubiquitin-like proteins in Arabidopsis Thaliana ecotype Columbia. Genetics. 1995;139:921-939. DOI: 10.6731/PMID.7713442
  8. 8. Vijay-Kumar S, Bugg CE, Cook WJ. Structure of ubiquitin refined at 1.8 a resolution. Journal of Molecular Biology. 1987;194:531-544. DOI: 10.1016/0022-2836(87)90679-6
  9. 9. Smalle J, Vierstra RD. The ubiquitin 26S proteasome proteolytic pathway. Annual Review of Plant Biology. 2004;55:555-590. DOI: 10.1146/annurev.arplant.55.031903.141801
  10. 10. Koepp DM, Harper JW, Elledge SJ. How the cyclin became a cyclin: Regulated proteolysis in the cell cycle. Cell. 1999;97:431-434. DOI: 10.1016/S0092-8674(00)80753-9
  11. 11. Hofmann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell. 1999;96:645-653. DOI: 10.1016/S0092-8674(00)80575-9
  12. 12. Ghosh S, May MJ, Kopp EB, NF-kappa B. Rel proteins: Evolutionarily conserved mediators of immune responses. Annual Review of Immunology. 1998;16:225-260. DOI: 10.1146/annurev.immunol.16.1.225
  13. 13. Zhang Y. Transcriptional regulation by histone ubiquitination and deubiquitination. Genes & Development. 2003;17:2733-2740. DOI: 10.1101/gad.1156403
  14. 14. Shilatifard A. Chromatin modifications by methylation and ubiquitination: Implications in the regulation of gene expression. Annual Review of Biochemistry. 2006;75:243-269. DOI: 10.1146/annurev.biochem.75.103004.142422
  15. 15. Puente XS, Lopez-Otin C. A genomic analysis of rat proteases and protease inhibitors. Genome Research. 2004;14:609-622. DOI: 10.1101/gr.1946304
  16. 16. McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA, Gellert M, Oettinger MA. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell. 1995;83:387-395. DOI: 10.1016/0092-8674(95)90116-7
  17. 17. Gellert M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annual Review of Biochemistry. 2002;71:101-132. DOI: 10.1146/annurev.biochem.71.090501.150203
  18. 18. Grawunder U, Harfst E. How to make ends meet in V(D)J recombination. Current Opinion in Immunology. 2001;13:186-194. DOI: 10.1016/S0952-7915(00)00203-X
  19. 19. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiological Reviews. 1979;59:527-605. DOI: 10.9333/PMID.7713442
  20. 20. Lieber MR, Ma Y, Pannicke U, Schwarz K. Mechanism and regulation of human non-homologous DNA end-joining. Nature Reviews. Molecular Cell Biology. 2003;4:712-720. DOI: 10.1038/nrm1202
  21. 21. Kellner U, Sehested M, Jensen PB, Gieseler F, Rudolph P. Culprit and victim -- DNA topoisomerase II. The Lancet Oncology. 2002;3:235-243. DOI: 10.1016/S1470-2045(02)00715-5
  22. 22. Murnane JP. Telomeres and chromosome instability. DNA Repair (Amst). 2006;5:1082-1092. DOI: 10.1016/j.dnarep.2006.05.030
  23. 23. Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD, Panier S, Mendez M, Wildenhain J, Thomson TM, Pelletier L, Jackson SP, Durocher D. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science. 2007;318:1637-1640. DOI: 10.1126/science.1150034
  24. 24. Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell. 2007;131:901-914. DOI: 10.1016/j.cell.2007.09.041
  25. 25. Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell. 2007;131:887-900. DOI: 10.1016/j.cell.2007.09.040
  26. 26. Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen DH, Pepperkok R, Ellenberg J, Panier S, Durocher D, Bartek J, Lukas J, Lukas C. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009;136:435-446. DOI: 10.1016/j.cell.2008.12.041
  27. 27. Reinhardt HC, Yaffe MB. Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Current Opinion in Cell Biology. 2009;21:245-255. DOI: 10.1016/
  28. 28. Takai H, Naka K, Okada Y, Watanabe M, Harada N, Saito S, Anderson CW, Appella E, Nakanishi M, Suzuki H, Nagashima K, Sawa H, Ikeda K, Motoyama N. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. The EMBO Journal. 2002;21:5195-5205. DOI: 10.1093/emboj/cdf506
  29. 29. Rich T, Allen RL, Wyllie AH. Defying death after DNA damage. Nature. 2000;407:777-783. DOI: 10.1038/35037717
  30. 30. Ferguson DO, Alt FW. DNA double strand break repair and chromosomal translocation: Lessons from animal models. Oncogene. 2001;20:5572-5579. DOI: 10.1038/sj.onc.1204767
  31. 31. Gottlieb TM, Jackson SP. The DNA-dependent protein kinase: Requirement for DNA ends and association with Ku antigen. Cell. 1993;72:131-142. DOI: 10.1016/0092-8674(93)90057-W
  32. 32. Ramsden DA, Gellert M. Ku protein stimulates DNA end joining by mammalian DNA ligases: A direct role for Ku in repair of DNA double-strand breaks. The EMBO Journal. 1998;17:609-614. DOI: 10.1093/emboj/17.2.609
  33. 33. Brouwer I, Sitters G, Candelli A, Heerema SJ, Heller I, de Melo AJ, Zhang H, Normanno D, Modesti M, Peterman EJ, Wuite GJ. Sliding sleeves of XRCC4-XLF bridge DNA and connect fragments of broken DNA. Nature. 2016;535:566-569. DOI: 10.1038/nature18643
  34. 34. Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, Tezcan I, Sanal O, Bertrand Y, Philippe N, Fischer A, de Villartay JP. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell. 2001;105:177-186. DOI: 10.1016/S0092-8674(01)00309-9
  35. 35. Ma Y, Pannicke U, Schwarz K, Lieber MR. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell. 2002;108:781-794. DOI: 10.1016/S0092-8674(02)00671-2
  36. 36. O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Molecular Cell. 2001;8:1175-1185. DOI: 10.1016/S1097-2765(01)00408-7
  37. 37. Game JCDNA. Double-strand breaks and the RAD50-RAD57 genes in saccharomyces. Seminars in Cancer Biology. 1993;4:73-83. DOI: 10.579X/PMID.8513150
  38. 38. Johnson RD, Jasin M. Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. The EMBO Journal. 2000;19:3398-3407. DOI: 10.1093/emboj/19.13.3398
  39. 39. Iftode C, Daniely Y, Borowiec JA. Replication protein a (RPA): The eukaryotic SSB. Critical Reviews in Biochemistry and Molecular Biology. 1999;34:141-180. DOI: 10.1080/10409239991209255
  40. 40. Jackson D, Dhar K, Wahl JK, Wold MS, Borgstahl GE. Analysis of the human replication protein a:Rad52 complex: Evidence for crosstalk between RPA32, RPA70, Rad52 and DNA. Journal of Molecular Biology. 2002;321:133-148. DOI: 10.1016/S0022-2836(02)00541-7
  41. 41. Gasior SL, Olivares H, Ear U, Hari DM, Weichselbaum R, Bishop DK. Assembly of RecA-like recombinases: Distinct roles for mediator proteins in mitosis and meiosis. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:8411-8418. DOI: 10.1073/pnas.121046198
  42. 42. Morrison C, Sonoda E, Takao N, Shinohara A, Yamamoto K, Takeda S. The controlling role of ATM in homologous recombinational repair of DNA damage. The EMBO Journal. 2000;19:463-471. DOI: 10.1093/emboj/19.3.463
  43. 43. Ahlskog JK, Larsen BD, Achanta K, Sorensen CS. ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function. EMBO Reports. 2016;17:671-681. DOI: 10.15252/embr.201541455
  44. 44. Li M, Yu X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell. 2013;23:693-704. DOI: 10.1016/j.ccr.2013.03.025
  45. 45. Kim H, Chen J, Yu X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science. 2007;316:1202-1205. DOI: 10.1126/science.1139621
  46. 46. Coleman KA, Greenberg RA. The BRCA1-RAP80 complex regulates DNA repair mechanism utilization by restricting end resection. The Journal of Biological Chemistry. 2011;286:13669-13680. DOI: 10.1074/jbc.M110.213728
  47. 47. Thompson LH, Schild D. Recombinational DNA repair and human disease. Mutation Research. 2002;509:49-78. DOI: 10.1016/S0027-5107(02)00224-5
  48. 48. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123:773-786. DOI: 10.1016/j.cell.2005.11.007
  49. 49. Tobias JW, Varshavsky A. Cloning and functional analysis of the ubiquitin-specific protease gene UBP1 of Saccharomyces Cerevisiae. The Journal of Biological Chemistry. 1991;266:12021-12028. DOI: 10.9258/PMID.2050695
  50. 50. Hu M, Li P, Li M, Li W, Yao T, Wu JW, Gu W, Cohen RE, Shi Y. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 2002;111:1041-1054. DOI: S0092-8674(02)01199-6
  51. 51. Komander D, Lord CJ, Scheel H, Swift S, Hofmann K, Ashworth A, Barford D. The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Molecular Cell. 2008;29:451-464. DOI: 10.1016/j.molcel.2007.12.018
  52. 52. Ye Y, Scheel H, Hofmann K, Komander D. Dissection of USP catalytic domains reveals five common insertion points. Molecular BioSystems. 2009;5:1797-1808. DOI: 10.1039/b907669g
  53. 53. Daviet L, Colland F. Targeting ubiquitin specific proteases for drug discovery. Biochimie. 2008;90:270-283. DOI: 10.1016/j.biochi.2007.09.013
  54. 54. Williams SA, Maecker HL, French DM, Liu J, Gregg A, Silverstein LB, Cao TC, Carano RA, Dixit VM. USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell. 2011;146:918-930. DOI: 10.1016/j.cell.2011.07.040
  55. 55. Garcia-Santisteban I, Peters GJ, Giovannetti E, Rodriguez JA. USP1 deubiquitinase: Cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy. Molecular Cancer. 2013;12:91. DOI: 10.1186/1476-4598-12-91
  56. 56. Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D’Andrea AD. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Molecular Cell. 2007;28:786-797. DOI: 10.1016/j.molcel.2007.09.031
  57. 57. Murai J, Yang K, Dejsuphong D, Hirota K, Takeda S, D’Andrea AD. The USP1/UAF1 complex promotes double-strand break repair through homologous recombination. Molecular and Cellular Biology. 2011;31:2462-2469. DOI: 10.1128/MCB.05058-11
  58. 58. Nicassio F, Corrado N, Vissers JH, Areces LB, Bergink S, Marteijn JA, Geverts B, Houtsmuller AB, Vermeulen W, Di Fiore PP, Citterio E. Human USP3 is a chromatin modifier required for S phase progression and genome stability. Current Biology. 2007;17:1972-1977. DOI: 10.1016/j.cub.2007.10.034
  59. 59. Sloper-Mould KE, Eyre HJ, Wang XW, Sutherland GR, Baker RT. Characterization and chromosomal localization of USP3, a novel human ubiquitin-specific protease. The Journal of Biological Chemistry. 1999;274:26878-26884. DOI: 10.1074/jbc.274.38.26878
  60. 60. Lancini C, van den Berk PC, Vissers JH, Gargiulo G, Song JY, Hulsman D, Serresi M, Tanger E, Blom M, Vens C, van Lohuizen M, Jacobs H, Citterio E. Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells. The Journal of Experimental Medicine. 2014;211:1759-1777. DOI: 10.1084/jem.20131436
  61. 61. Sharma N, Zhu Q, Wani G, He J, Wang QE, Wani AA. USP3 counteracts RNF168 via deubiquitinating H2A and gammaH2AX at lysine 13 and 15. Cell Cycle. 2014;13:106-114. DOI: 10.4161/cc.26814
  62. 62. Wang Z, Zhang H, Liu J, Cheruiyot A, Lee JH, Ordog T, Lou Z, You Z, Zhang Z. USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response. Genes & Development. 2016;30:946-959. DOI: 10.1101/gad.271841.115
  63. 63. Mosbech A, Lukas C, Bekker-Jensen S, Mailand N. The deubiquitylating enzyme USP44 counteracts the DNA double-strand break response mediated by the RNF8 and RNF168 ubiquitin ligases. The Journal of Biological Chemistry. 2013;288:16579-16587. DOI: 10.1074/jbc.M113.459917
  64. 64. Atanassov BS, Mohan RD, Lan X, Kuang X, Lu Y, Lin K, McIvor E, Li W, Zhang Y, Florens L, Byrum SD, Mackintosh SG, Calhoun-Davis T, Koutelou E, Wang L, Tang DG, Tackett AJ, Washburn MP, Workman JL, Dent SY. ATXN7L3 and ENY2 coordinate activity of multiple H2B Deubiquitinases important for cellular proliferation and tumor growth. Molecular Cell. 2016;62:558-571. DOI: 10.1016/j.molcel.2016.03.030
  65. 65. Gray DA, Inazawa J, Gupta K, Wong A, Ueda R, Takahashi T. Elevated expression of Unph, a proto-oncogene at 3p21.3, in human lung tumors. Oncogene. 1995;10:2179-2183. DOI: 10.9232/PMID.7784062
  66. 66. Gilchrist CA, Baker RT. Characterization of the ubiquitin-specific protease activity of the mouse/human Unp/Unph oncoprotein. Biochimica et Biophysica Acta. 2000;1481:297-309. DOI: 10.3002/PMID.11018721
  67. 67. Zhang X, Berger FG, Yang J, Lu X. USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. The EMBO Journal. 2011;30:2177-2189. DOI: 10.1038/emboj.2011.125
  68. 68. Heo MJ, Kim YM, Koo JH, Yang YM, An J, Lee SK, Lee SJ, Kim KM, Park JW, Kim SG. microRNA-148a dysregulation discriminates poor prognosis of hepatocellular carcinoma in association with USP4 overexpression. Oncotarget. 2014;5:2792-2806. DOI: 10.18632/oncotarget.1920
  69. 69. Liu H, Zhang H, Wang X, Tian Q, Hu Z, Peng C, Jiang P, Wang T, Guo W, Chen Y, Li X, Zhang P, Pei H. The Deubiquitylating enzyme USP4 cooperates with CtIP in DNA double-strand break end resection. Cell Reports. 2015;13:93-107. DOI: 10.1016/j.celrep.2015.08.056
  70. 70. Wijnhoven P, Konietzny R, Blackford AN, Travers J, Kessler BM, Nishi R, Jackson SP. USP4 auto-Deubiquitylation promotes homologous recombination. Molecular Cell. 2015;60:362-373. DOI: 10.1016/j.molcel.2015.09.019
  71. 71. Zhu X, Menard R, Sulea T. High incidence of ubiquitin-like domains in human ubiquitin-specific proteases. Proteins. 2007;69:1-7. DOI: 10.1002/prot.21546
  72. 72. Vlasschaert C, Xia X, Coulombe J, Gray DA. Evolution of the highly networked deubiquitinating enzymes USP4, USP15, and USP11. BMC Evolutionary Biology. 2015;15:230. DOI: 10.1186/s12862-015-0511-1
  73. 73. Wiltshire TD, Lovejoy CA, Wang T, Xia F, O’Connor MJ, Cortez D. Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. The Journal of Biological Chemistry. 2010;285:14565-14571. DOI: 10.1074/jbc.M110.104745
  74. 74. Zou Q, Jin J, Hu H, Li HS, Romano S, Xiao Y, Nakaya M, Zhou X, Cheng X, Yang P, Lozano G, Zhu C, Watowich SS, Ullrich SE, Sun SC. USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nature Immunology. 2014;15:562-570. DOI: 10.1038/ni.2885
  75. 75. Lahav-Baratz S, Kravtsova-Ivantsiv Y, Golan S, Ciechanover A. The testis-specific USP26 is a deubiquitinating enzyme of the ubiquitin ligase Mdm2. Biochemical and Biophysical Research Communications. 2017;482:106-111. DOI: 10.1016/j.bbrc.2016.10.135
  76. 76. Typas D, Luijsterburg MS, Wiegant WW, Diakatou M, Helfricht A, Thijssen PE, van den Broek B, Mullenders LH, van Attikum H. The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80. Nucleic Acids Research. 2015;43:6919-6933. DOI: 10.1093/nar/gkv613
  77. 77. Vucic D, Dixit VM, Wertz IE. Ubiquitylation in apoptosis: A post-translational modification at the edge of life and death. Nature Reviews. Molecular Cell Biology. 2011;12:439-452. DOI: 10.1038/nrm3143
  78. 78. Faustrup H, Bekker-Jensen S, Bartek J, Lukas J, Mailand N. USP7 counteracts SCFbetaTrCP- but not APCCdh1-mediated proteolysis of Claspin. The Journal of Cell Biology. 2009;184:13-19. DOI: 10.1083/jcb.200807137
  79. 79. Sacco JJ, Coulson JM, Clague MJ, Urbe S. Emerging roles of deubiquitinases in cancer-associated pathways. IUBMB Life. 2010;62:140-157. DOI: 10.1002/iub.300
  80. 80. Yuan J, Luo K, Deng M, Li Y, Yin P, Gao B, Fang Y, Wu P, Liu T, Lou Z. HERC2-USP20 axis regulates DNA damage checkpoint through Claspin. Nucleic Acids Research. 2014;42:13110-13121. DOI: 10.1093/nar/gku1034
  81. 81. Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle. 2005;4:1166-1170. DOI: 10.4161/cc.4.9.1981
  82. 82. Hu M, Gu L, Li M, Jeffrey PD, Gu W, Shi Y. Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: Implications for the regulation of the p53-MDM2 pathway. PLoS Biology. 2006;4:e27. DOI: 10.1371/journal.pbio.0040027
  83. 83. Alonso-de Vega I, Martin Y, Smits VA. USP7 controls Chk1 protein stability by direct deubiquitination. Cell Cycle. 2014;13:3921-3926. DOI: 10.4161/15384101.2014.973324
  84. 84. Yuan J, Luo K, Zhang L, Cheville JC, Lou Z. USP10 regulates p53 localization and stability by deubiquitinating p53. Cell. 2010;140:384-396. DOI: 10.1016/j.cell.2009.12.032
  85. 85. Liu J, Chung HJ, Vogt M, Jin Y, Malide D, He L, Dundr M, Levens D. JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. The EMBO Journal. 2011;30:846-858. DOI: 10.1038/emboj.2011.11
  86. 86. Hock AK, Vigneron AM, Carter S, Ludwig RL, Vousden KH. Regulation of p53 stability and function by the deubiquitinating enzyme USP42. The EMBO Journal. 2011;30:4921-4930. DOI: 10.1038/emboj.2011.419
  87. 87. Sun XX, Dai MS. Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1. World Journal of Biological Chemistry. 2014;5:75-84. DOI: 10.4331/wjbc.v5.i2.75
  88. 88. Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O’Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras AC, Natsume T, Suda T, Durocher D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 2010;466:941-946. DOI: 10.1038/nature09297
  89. 89. Luo J, Lu Z, Lu X, Chen L, Cao J, Zhang S, Ling Y, Zhou X. OTUD5 regulates p53 stability by deubiquitinating p53. PLoS One. 2013;8:e77682. DOI: 10.1371/journal.pone.0077682
  90. 90. Butler LR, Densham RM, Jia J, Garvin AJ, Stone HR, Shah V, Weekes D, Festy F, Beesley J, Morris JR. The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. The EMBO Journal. 2012;31:3918-3934. DOI: 10.1038/emboj.2012.232
  91. 91. Komander D, Clague MJ, Urbe S. Breaking the chains: Structure and function of the deubiquitinases. Nature Reviews. Molecular Cell Biology. 2009;10:550-563. DOI: 10.1038/nrm2731
  92. 92. Balakirev MY, Tcherniuk SO, Jaquinod M, Chroboczek J. Otubains: A new family of cysteine proteases in the ubiquitin pathway. EMBO Reports. 2003;4:517-522. DOI: 10.1038/sj.embor.embor824
  93. 93. Nanao MH, Tcherniuk SO, Chroboczek J, Dideberg O, Dessen A, Balakirev MY. Crystal structure of human otubain 2. EMBO Reports. 2004;5:783-788. DOI: 10.1038/sj.embor.7400201
  94. 94. Wang T, Yin L, Cooper EM, Lai MY, Dickey S, Pickart CM, Fushman D, Wilkinson KD, Cohen RE, Wolberger C. Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1. Journal of Molecular Biology. 2009;386:1011-1023. DOI: 10.1016/j.jmb.2008.12.085
  95. 95. Li S, Zheng H, Mao AP, Zhong B, Li Y, Liu Y, Gao Y, Ran Y, Tien P, Shu HB. Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. The Journal of Biological Chemistry. 2010;285:4291-4297. DOI: 10.1074/jbc.M109.074971
  96. 96. Soares L, Seroogy C, Skrenta H, Anandasabapathy N, Lovelace P, Chung CD, Engleman E, Fathman CG. Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nature Immunology. 2004;5:45-54. DOI: 10.1038/ni1017
  97. 97. Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O’Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM. DUBA: A deubiquitinase that regulates type I interferon production. Science. 2007;318:1628-1632. DOI: 10.1126/science.1145918
  98. 98. Baietti MF, Simicek M, Abbasi Asbagh L, Radaelli E, Lievens S, Crowther J, Steklov M, Aushev VN, Martinez Garcia D, Tavernier J, Sablina AA. OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination. EMBO Molecular Medicine. 2016;8:288-303. DOI: 10.15252/emmm.201505972
  99. 99. Zhou Y, Wu J, Fu X, Du W, Zhou L, Meng X, Yu H, Lin J, Ye W, Liu J, Peng H, Liu RY, Pan C, Huang W. OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer. Molecular Cancer. 2014;13:258. DOI: 10.1186/1476-4598-13-258
  100. 100. Liu X, Jiang WN, Wang JG, Chen H. Colon Cancer bears overexpression of OTUB1. Pathology, Research and Practice. 2014;210:770-773. DOI: 10.1016/j.prp.2014.05.008
  101. 101. Tran HJ, Allen MD, Lowe J, Bycroft M. Structure of the Jab1/MPN domain and its implications for proteasome function. Biochemistry. 2003;42:11460-11465. DOI: 10.1021/bi035033g

Written By

Jun Lu, Zhi-Feng Xi, Xiao-Ying Huang, Qiang Xia and Xi-Dai Long

Submitted: December 20th, 2016 Reviewed: December 21st, 2017 Published: January 26th, 2018