USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15

Sharma, Nidhi; Zhu, Qianzheng; Wani, Gulzar; He, Jingshan; Wang, Qi-En; Wani, Altaf A.

doi:10.4161/cc.26814

Cited by 99 publications

(102 citation statements)

References 34 publications

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“…40 Accordingly, we wondered whether expressing a ubiquitin-histone H2AX fusion protein in cells deficient for RNF8 or RNF168 would rescue 53BP1 recruitment to IR-induced foci (IRIF). We first examined RNF8-/-mouse embryo fibroblasts (MEFs).…”

Section: Resultsmentioning

confidence: 99%

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

et al. 2015

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The mammalian E3 ubiquitin ligases RNF8 and RNF168 facilitate recruitment of the DNA damage response protein 53BP1 to sites of DNA double-strand breaks (DSBs). The mechanism involves recruitment of RNF8, followed by recruitment of RNF168, which ubiquitinates histones H2A/H2AX on K15. 53BP1 then binds to nucleosomes at sites of DNA DSBs by recognizing, in addition to methyl marks, histone H2A/H2AX ubiquitinated on K15. We report here that expressing H2AX fusion proteins with N-terminal bulky moieties can rescue 53BP1 recruitment to sites of DNA DSBs in cells lacking RNF8 or RNF168 or in cells treated with proteasome inhibitors, in which histone ubiquitination at sites of DNA DSBs is compromised. The rescue required S139 at the C-terminus of the H2AX fusion protein and was occasionally accompanied by partial rescue of ubiquitination at sites of DNA DSBs. We conclude that recruitment of 53BP1 to sites of DNA DSBs is possible in the absence of RNF8 or RNF168, but still dependent on chromatin ubiquitination.

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Section: Resultsmentioning

confidence: 99%

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

et al. 2015

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“…Multiple deubiquitinating enzymes were proposed to remove monomeric ubiquitin from K119 and K13/K15 of H2A and therefore it is likely that there is some redundancy in controlling histone deubiquitination. [52][53][54] Among these deubiquitinating enzymes USP3 and USP16 were reported to be regulated by mitotic events. USP3 associates with the chromatin and has the ability to deubiquitinate both K119 and K13/K15 of H2A.…”

Section: Discussionmentioning

confidence: 99%

Polo-like kinase 1 inhibits DNA damage response during mitosis

et al. 2015

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Abbreviations: 53BP1, p53 binding protein 1; ATM, ataxia telangiectasia mutated kinase; BRCA1, breast cancer type 1 susceptibility protein; Cdk, cyclin dependent kinase; DDR, DNA damage response; Plk1, Polo-like kinase 1; H2AX, histone variant H2AX; IR -ionizing radiation; MDC1, mediator of DNA damage checkpoint protein 1; NCS -neocarzinostatin; NZ -nocodazole; PTIP, PAX transactivation activation domain-interacting protein; RIF1, Rap1-interacting factor 1 homolog; RNAi, RNA interference; RNF8, RING finger protein 8; RNF168, RING finger protein 168.In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage response (DDR) pathway that coordinates DNA repair and progression through the cell cycle. Extensive modification of the chromatin flanking the DNA lesion by ATM kinase and RNF8/RNF168 ubiquitin ligases enables recruitment of various repair factors. Among them BRCA1 and 53BP1 are required for homologous recombination and nonhomologous end joining, respectively. Whereas mechanisms of DDR are relatively well understood in interphase cells, comparatively less is known about organization of DDR during mitosis. Although ATM can be activated in mitotic cells, 53BP1 is not recruited to the chromatin until cells exit mitosis. Here we report mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 that impairs the ability of 53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage. Phosphorylation of 53BP1 at S1618 occurs at kinetochores and in cytosol and is restricted to mitotic cells. Interaction between 53BP1 and Plk1 depends on the activity of Cdk1. We propose that activity of Cdk1 and Plk1 allows spatiotemporally controlled suppression of 53BP1 function during mitosis.

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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%

“…It is known that USP16 targets H2AK119ub and H2AK15ub and that USP3 targets H2AK15ub (Sharma et al 2014;Zhang et al 2014). To gain insight into how USP51 functions in DDR, we compared the effect of overexpression of USP3, USP16, and USP51 on the formation of IR-induced 53BP1 and RNF168 foci.…”

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.…”

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confidence: 99%

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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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USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15

Abstract: A Wani (2014) USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15, Cell Cycle, 13:1, 106-114,

Cited by 99 publications

References 34 publications

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

Polo-like kinase 1 inhibits DNA damage response during mitosis

USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response

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