The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

Baranes-Bachar, Keren; Levy‐Barda, Adva; Oehler, Judith; Reid, Dylan A.; Soria‐Bretones, Isabel; Voss, Ty C.; Chung, Dudley; Park, Yoon; Liu, Chao; Yoon, Jong Bok; Li, Wei; Dellaire, Graham; Misteli, Tom; Huertas, Pablo; Rothenberg, Eli; Ramadan, Kristijan; Ziv, Yael; Shiloh, Yosef

doi:10.1016/j.molcel.2018.02.002

Cited by 43 publications

(44 citation statements)

References 75 publications

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“…MG132 treatment led to the accumulation of RNF8 (Appendix Fig S1M and N), which further supports that the turnover of RNF8 from sites of DNA damage is a ubiquitin‐dependent process. Strikingly, depletion of p97 increased the accumulation of both K48‐Ub (Fig EV4A and B) and K63‐Ub (Fig I and J) at sites of DNA damage (Baranes‐Bachar et al , ), indicating that several different substrates of p97 are accumulating in its absence. However, inactivation of ATX3 only increased the accumulation of K63‐Ub at sites of DNA damage.…”

Section: Resultsmentioning

confidence: 90%

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

et al. 2019

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The E3 ubiquitin ligase RNF8 (RING finger protein 8) is a pivotal enzyme for DNA repair. However, RNF8 hyper‐accumulation is tumour‐promoting and positively correlates with genome instability, cancer cell invasion, metastasis and poor patient prognosis. Very little is known about the mechanisms regulating RNF8 homeostasis to preserve genome stability. Here, we identify the cellular machinery, composed of the p97/VCP ubiquitin‐dependent unfoldase/segregase and the Ataxin 3 (ATX3) deubiquitinase, which together form a physical and functional complex with RNF8 to regulate its proteasome‐dependent homeostasis under physiological conditions. Under genotoxic stress, when RNF8 is rapidly recruited to sites of DNA lesions, the p97–ATX3 machinery stimulates the extraction of RNF8 from chromatin to balance DNA repair pathway choice and promote cell survival after ionising radiation (IR). Inactivation of the p97–ATX3 complex affects the non‐homologous end joining DNA repair pathway and hypersensitises human cancer cells to IR. We propose that the p97–ATX3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions and that targeting ATX3 may be a promising strategy to radio‐sensitise BRCA‐deficient cancers.

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Section: Resultsmentioning

confidence: 90%

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

et al. 2019

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“…Previous work has identified OTUB2 as a negative regulator of the core ubiquitin ligase RNF8, where it suppresses RNF8 activity to promote high-fidelity HR repair ( 75 ). The importance of maintaining optimal RNF8 output was also unveiled recently with the identification of the E3/E4 ligase UBE4A, which enforces DSB signal output to promote optimal DSB resection and HR repair ( 76 ). Although it remains to be seen if RNF169 may have additional roles in DSB response control, our data adds an additional regulatory layer of DSB signal output and firmly establish the interplay of RNF169 and 53BP1/RAP80 as active regulators of DSB repair pathway choice.…”

Section: Discussionmentioning

confidence: 99%

RNF169 limits 53BP1 deposition at DSBs to stimulate single-strand annealing repair

Dong

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Significance53BP1 restrains DNA end resection, and its dosage imbalance upsets DNA double-strand break (DSB) repair pathway choice. Here, by monitoring 53BP1 distribution on DSB-flanking chromatin, we have established a dose-dependent role of the RING finger protein RNF169 in limiting 53BP1 DSB deposition. Moreover, we found that forced expression of RNF169 overcomes 53BP1 activity and stimulates mutagenic DSB repair via the single-strand annealing pathway. Our findings suggest that aberrant expression of RNF169 may represent a deleterious factor in DSB repair control and in maintenance of genome stability.

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“…Among the three best-characterized BRCA1-containing complexes, BRCA1-B (TopBP1/BACH1) and -C (MRN/CtIP) complexes localize to sites of DNA damage mainly through pathways involving PARP1-mediated PARsylation (28) to promote end resection, which can activate HRR (15,16,20,39). On the other hand, the BRCA1-A complex (Abraxas/RAP80), which is phospho-H2AX-dependent, likely accumulates at these DNA damage sites, where it can inhibit end resection (29)(30)(31)40), conceivably via a process mediated by precise protein ubiquitination and deubiquitination (23,41,42). Interestingly, we previously showed that BRCA1 is also modified by PARP1, which is required for the stable formation of BRCA1-A (Abraxas/RAP80) complex (21).…”

Section: Brca1 Overexpression Is Associated With Aneuploidy and Poormentioning

confidence: 99%

RAP80 and BRCA1 PARsylation protect chromosome integrity by preventing retention of BRCA1-B/C complexes in DNA repair foci

Vohhodina

Toomire

Petit

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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BRCA1 promotes error-free, homologous recombination-mediated repair (HRR) of DNA double-stranded breaks (DSBs). When excessive and uncontrolled, BRCA1 HRR activity promotes illegitimate recombination and genome disorder. We and others have observed that the BRCA1-associated protein RAP80 recruits BRCA1 to postdamage nuclear foci, and these chromatin structures then restrict the amplitude of BRCA1-driven HRR. What remains unclear is how this process is regulated. Here we report that both BRCA1 poly-ADP ribosylation (PARsylation) and the presence of BRCA1-bound RAP80 are critical for the normal interaction of BRCA1 with some of its partners (e.g., CtIP and BACH1) that are also known components of the aforementioned focal structures. Surprisingly, the simultaneous loss of RAP80 and failure therein of BRCA1 PARsylation results in the dysregulated accumulation in these foci of BRCA1 complexes. This in turn is associated with the intracellular development of a state of hyper-recombination and gross chromosomal disorder. Thus, physiological RAP80-BRCA1 complex formation and BRCA1 PARsylation contribute to the kinetics by which BRCA1 HRR-sustaining complexes normally concentrate in nuclear foci. These events likely contribute to aneuploidy suppression.

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The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

Cited by 43 publications

References 75 publications

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

RNF169 limits 53BP1 deposition at DSBs to stimulate single-strand annealing repair

RAP80 and BRCA1 PARsylation protect chromosome integrity by preventing retention of BRCA1-B/C complexes in DNA repair foci

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