Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells

Lancini, Cesare; Berk, Paul C.M. van den; Vissers, Jmh Jan; Gargiulo, Gaetano; Song, Ji‐Ying; Hulsman, Danielle; Serresi, Michela; Tanger, Ellen; Blom, Marleen; Vens, Conchita; Lohuizen, Maarten van; Jacobs, Heinz; Citterio, Elisabetta

doi:10.1084/jem.20131436

Cited by 72 publications

(77 citation statements)

References 74 publications

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“…Although several DUBs are required for both DNA repair and cell viability after irradiation (Delgado-Díaz et al, 2014;Ismail et al, 2014;Lancini et al, 2014;Nishi et al, 2014), the role of DUBs in checkpoint silencing and cell cycle restart after DNA damage remains to be addressed. Of the 32 DUBs found to localise to sites of DNA damage, 13 appear to be dispensable for overall DNA repair, as judged by single-cell gel electrophoresis, with depletion of USP4, USP37 or POH1 affecting checkpoint kinase signalling.…”

Section: Consequences For Recoverymentioning

confidence: 99%

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Shaltiël

Krenning

Bruinsma

et al. 2015

Journal of Cell Science

252

272

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Cell cycle checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-damageinduced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA damage checkpoints, before discussing when and how cell fate decisions after a DSB are made.

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Section: Consequences For Recoverymentioning

confidence: 99%

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Shaltiël

Krenning

Bruinsma

et al. 2015

Journal of Cell Science

252

272

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“…USP3, USP16, and USP51 function distinctly in response to IR-induced DNA breaks Previous studies have shown that two other DUBs, USP3 and USP16, are also involved in DDR (Nicassio et al 2007;Lancini et al 2014;Sharma et al 2014). It is known that USP16 targets H2AK119ub and H2AK15ub and that USP3 targets H2AK15ub (Sharma et al 2014;Zhang et al 2014).…”

Section: Usp51 Functions Downstream From Mdc1 Recruitment In Responsementioning

confidence: 99%

“…In addition, several other DUBs have been shown to be involved in DDR. For instance, USP3 and USP44 have been suggested to counteract DSB-induced histone ubiquitylation (Nicassio et al 2007;Doil et al 2009;Mosbech et al 2013;Lancini et al 2014;Sharma et al 2014). Overexpression of USP3 and USP44 affects the localization of RNF168 at DSB sites, suggesting that these two DUBs regulate ubiquitylation upstream of RNF168.…”

mentioning

confidence: 99%

USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response

et al. 2016

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Dynamic regulation of RNF168-mediated ubiquitylation of histone H2A Lys13,15 (H2AK13,15ub) at DNA doublestrand breaks (DSBs) is crucial for preventing aberrant DNA repair and maintaining genome stability. However, it remains unclear which deubiquitylating enzyme (DUB) removes H2AK13,15ub. Here we show that USP51, a previously uncharacterized DUB, deubiquitylates H2AK13,15ub and regulates DNA damage response. USP51 depletion results in increased spontaneous DNA damage foci and elevated levels of H2AK15ub and impairs DNA damage response. USP51 overexpression suppresses the formation of ionizing radiation-induced 53BP1 and BRCA1 but not RNF168 foci, suggesting that USP51 functions downstream from RNF168 in DNA damage response. In vitro, USP51 binds to H2A-H2B directly and deubiquitylates H2AK13,15ub. In cells, USP51 is recruited to chromatin after DNA damage and regulates the dynamic assembly/disassembly of 53BP1 and BRCA1 foci. These results show that USP51 is the DUB for H2AK13,15ub and regulates DNA damage response.

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“…It is possible that USP3 also regulates H2B-ubiquitin, similar to its yeast homolog Ubp8, which is based upon the reduction of H2B-ubiquitin upon USP3 overexpression observed in another study (82). The in vivo significance of USP3 function was demonstrated by studies with mice deficient in Usp3 (usp3⌬/⌬ [83]). The cells from usp3 knockout mice display an increased level of H2A-Ub, and spontaneous focus formation of Ub chains (FK2), 53BP1, and ␥-H2AX, suggesting that the DSB signaling is increased and genome integrity is compromised.…”

Section: Dubs That Modulate Dsb Repair Signalingmentioning

confidence: 92%

“…Similarly, USP9x inhibition cannot induce apoptosis only by destabilizing antiapoptotic MCL1 (236), but the apoptotic effect can also be further potentiated by combining with a DNA-alkylating agent based upon its role in stabilizing ALKBH3 (229). As for many other therapeutic approaches of targeting DNA repair pathways, potential complications arising with spontaneous tumor development in the long run should be taken into consideration when inhibiting DUBs in DNA repair; for example, USP3 and USP44 knockout mice were born healthy, but they ultimately develop tumors (83,87).…”

Section: Future Perspectivesmentioning

confidence: 99%

Role of Deubiquitinating Enzymes in DNA Repair

Kee

Huang

2016

Molecular and Cellular Biology

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Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling. DEUBIQUITINATING ENZYMES Safeguarding the genome from genotoxic stress is critical for cell survival and for preventing various human diseases, including cancer. DNA repair or DNA damage responses are under exquisite control and must be accurately and rapidly executed when genome integrity is challenged. Understanding the molecular mechanisms and regulation of critical DNA repair and damage response factors in mammalian cells will provide insight into the pathogenesis of human diseases and aid in the development of therapeutics. Ubiquitination is a posttranslational modification event that allows for rapid and dynamic changes in a protein fate or function. The ubiquitin-proteasome system (UPS) is an essential posttranslational regulatory mechanism that permeates into diverse biological processes, including the DNA repair and damage response pathways. While the role of ubiquitin in mediating controlled degradation/proteolysis of specific proteins is well established, nonproteolytic functions of ubiquitination have also emerged as important players in signaling pathways that often exist in parallel with the UPS. Deubiquitinating enzymes (DUBs), responsible for reversing the ubiquitination reaction by removing covalently attached ubiquitin molecules from substrates or polyubiquitinated chains, have recently exploded onto the ubiquitin field as key regulators of both the UPS and of the nonproteolytic functions of ubiquitination. Thus, DUBs exert profound influence on many cellular pathways, including one of the best-studied biological processes involving DNA repair and damage response in mammalian cells.There are approximately 95 DUBs encoded by the human genome, which fall into one of the five subclasses: ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), Machado-Joseph domain-containing proteins (MJDs), Otubain domain-containing proteases (OTUs), and JAMM (JAB1/MPN/ Mov34) proteases (1, 2). Ubiquitin has seven internal lysine residues (Lys6,, each providing sites for the generation of an isopeptide bond with the carboxy terminus of another ubiquitin to form ubiquitin polymers, otherwise known as polyubiquitination. Linear ubiquitin chains can also be generated when the amino-terminal methionine (Met) of ubiquitin (Met1) forms a peptide bond with the carboxy-terminal glycine (Gly) of ubiquitin. As different types of polyubiquitin polymers adopt different conformations (3), it is not surprising that many DUBs show some degree of specificity toward differentially linked polyubiquitination, each of which results in a different physi...

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Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells

Abstract: In vivo deletion of USP3, a deubiquitinating enzyme involved in DNA damage repair, increases the incidence of spontaneous cancer and impairs the proliferation and repopulation ability of HSCs.

Cited by 72 publications

References 74 publications

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response

Role of Deubiquitinating Enzymes in DNA Repair

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