The role of ubiquitin-dependent segregase p97 (VCP or Cdc48) in chromatin dynamics after DNA double strand breaks

Torrecilla, Ignacio; Oehler, Judith; Ramadan, Kristijan

doi:10.1098/rstb.2016.0282

Cited by 53 publications

(43 citation statements)

References 147 publications

(243 reference statements)

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“…S2C). RNF4-dependent substrate ubiquitination is frequently followed by processing through VCP hexameric AAA ATPase (Dantuma et al 2014;Torrecilla et al 2017). We compared the effects of proteasome (MG132) or VCP inhibition (CB-5083) on MDC1 focus loss after IR.…”

Section: Rnf4-vcp Is Responsible For Defective Dna Damage Signaling Imentioning

confidence: 99%

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

et al. 2019

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SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.

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Section: Rnf4-vcp Is Responsible For Defective Dna Damage Signaling Imentioning

confidence: 99%

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

et al. 2019

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“…Another family of multi-SIM proteins, represented by the budding yeast Uls1 and fission yeast Rrp1/2, possess a SWI2/SNF2 ATPase domain and may be able to remove sumoylated proteins from chromatin via their potential translocase activities (Shah et al 2010;Lescasse et al 2013;Wei et al 2017). Yet another way to extract sumoylated pro-teins from chromatin or from protein association is mediated by the Cdc48 segregase (Torrecilla et al 2017). In both budding and fission yeasts, the Cdc48 cofactor Ufd1 uses its SIM sequences to recognize sumoylated proteins, targeting the segregase to specific substrates for their extraction and sometimes degradation (Bergink et al 2013;Kohler et al 2013).…”

mentioning

confidence: 99%

Intricate SUMO-based control of the homologous recombination machinery

Dhingra

Zhao

2019

Genes Dev.

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The homologous recombination (HR) machinery plays multiple roles in genome maintenance. Best studied in the context of DNA double-stranded break (DSB) repair, recombination enzymes can cleave, pair, and unwind DNA molecules, and collaborate with regulatory proteins to execute multiple DNA processing steps before generating specific repair products. HR proteins also help to cope with problems arising from DNA replication, modulating impaired replication forks or filling DNA gaps. Given these important roles, it is not surprising that each HR step is subject to complex regulation to adjust repair efficiency and outcomes as well as to limit toxic intermediates. Recent studies have revealed intricate regulation of all steps of HR by the protein modifier SUMO, which has been increasingly recognized for its broad influence in nuclear functions. This review aims to connect established roles of SUMO with its newly identified effects on recombinational repair and stimulate further thought on many unanswered questions.Homologous recombination is critical for several aspects of life, ranging from DNA repair and genome duplication to gamete production. Our understanding of HR pathways has benefited from a combination of assay systems. In cells, the generation of a defined DSB allows quantitative assessment of the status of the broken DNA molecules and the repair proteins at a temporal resolution, as well as determination of the genetic requirement for each step of repair (Haber 2016). Extensive biochemical analyses and more recently single molecule experiments have further defined the activities of HR enzymes and elucidated how they can collaborate in multiple HR steps. Several recent reviews have discussed these findings in detail (Symington et al. 2014;Heyer 2015;Ranjha et al. 2018); thus, we give only a brief overview here for each HR step to provide the context of SUMO-based regulation. As the HR machinery and its sumoylation are best examined in budding yeast, we use this system as an index for summarizing SUMO-based control. We also discuss additional regulation in mammalian cells and highlight their similarities and differences with those found in yeast. It is noteworthy that SUMO plays important roles in modulating protein recruitment to damaged chromatin and in other DNA break repair pathways. As these topics have been well covered in other reviews (Schwertman et al. 2016; Garvin and Morris 2017), they are not addressed here in order to maintain the focus on the regulation of core HR machinery.

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“…The human ortholog of Cdc48, p97/VCP, was recently reported to play a role in the DSB response (Torrecilla et al, 2017). The mammalian paralogs of Rad23, RAD23A and RAD23B are involved in the response to bulky DNA lesions via the nucleotide excision repair pathway (Yokoi and Hanaoka, 2017).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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Summary Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning - the E3/E4 ubiquitin ligase, UBE4A. UBE4A’s recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end-resection at DSBs, and its abrogation leads to up-regulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning of the complex DDR network for accurate and balanced execution of DSB repair.

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The role of ubiquitin-dependent segregase p97 (VCP or Cdc48) in chromatin dynamics after DNA double strand breaks

Cited by 53 publications

References 147 publications

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

Intricate SUMO-based control of the homologous recombination machinery

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

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