Sumoylation of MDC1 is important for proper DNA damage response

Luo, Kuntian; Zhang, Haoxing; Wang, Liewei; Yuan, Jian; Lou, Zhenkun

doi:10.1038/emboj.2012.158

Cited by 152 publications

(172 citation statements)

References 53 publications

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“…We used SILAC technology to study SUMOylation dynamics in response to IR and search for relevant RNF4 SUMO targets. Consistent with previous reports, 14,32 we identified 53BP1 and MDC1 as IR-induced SUMO-2 target proteins. To determine whether these SUMO conjugates are regulated by RNF4, knockdown experiments were performed in cells stably expressing low levels of His-SUMO-2.…”

Section: Resultssupporting

confidence: 80%

RNF4 is required for DNA double-strand break repair in vivo

et al. 2012

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Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiationinduced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events.

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Section: Resultssupporting

confidence: 80%

RNF4 is required for DNA double-strand break repair in vivo

et al. 2012

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“…The critical role for RNF4 at dysfunctional telomeres contrasts with its minor role at DNA DSBs induced by either ionizing radiation (IR) or laser irradiation [24][25][26]. Distinct from IR-induced DSBs that first evoke an ATM-dependent, and then rapidly following 5 0 -3 0 DNA resection, an ATR-dependent response [37], TRF2 depletion activates the ATM-but not the ATR-dependent pathway [12].…”

Section: Rnf4 Functions In the Atm-dependent Ddrmentioning

confidence: 99%

“…STUbL-dependent ubiquitination of SUMO conjugated target proteins, coupled or not with target degradation at the proteasome, drives key processes in the maintenance of genome stability [20][21][22][23]. The human STUbL RNF4 was recently demonstrated to act directly in DSB repair, by targeting multiple sumoylated proteins including MDC1, 53BP1 and BRCA1 [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

RNF 4 interacts with both SUMO and nucleosomes to promote the DNA damage response

et al. 2014

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The post-translational modification of DNA repair and checkpoint proteins by ubiquitin and small ubiquitin-like modifier (SUMO) critically orchestrates the DNA damage response (DDR). The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin, through its selective recognition and ubiquitination of SUMO-modified proteins. Here, we define a key new determinant for target discrimination by RNF4, in addition to interaction with SUMO. We identify a nucleosome-targeting motif within the RNF4 RING domain that can bind DNA and thereby enables RNF4 to selectively ubiquitinate nucleosomal histones. Furthermore, RNF4 nucleosome-targeting is crucially required for the repair of TRF2-depleted dysfunctional telomeres by 53BP1-mediated non-homologous end joining.

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“…The accumulation of SUMO at sites of DNA damage is important for the efficient recruitment of DDR proteins such as BRCA1 and 53BP1 Guzzo et al 2012;Hu et al 2012). Furthermore, a group of proteins involved in homologous recombination (HR), including BRCA1, MDC1, RPA70, and BLM, is directly modified by SUMO (Morris et al 2009;Ouyang et al 2009b;Dou et al 2010;Galanty et al 2012;Luo et al 2012;Yin et al 2012). SUMOylation regulates DDR proteins in several different ways.…”

mentioning

confidence: 99%

SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

Ouyang

Mori

et al. 2014

Genes Dev.

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The ATR (ATM [ataxia telangiectasia-mutated]-and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR-Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11-RAD50-NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway.[Keywords: ATR; ATRIP; checkpoint; SUMOylation] Supplemental material is available for this article.Received January 18, 2014; revised version accepted June 2, 2014.The maintenance of genomic stability requires not only DNA repair machineries but also signal transduction pathways that regulate and coordinate the DNA damage response (DDR) (Ciccia and Elledge 2010). In human cells, DNA damage signaling is primarily initiated by the ataxia telangiectasia-mutated (ATM) and the ATMand Rad3-related (ATR) kinases. Whereas ATM is activated by DNA double-stranded breaks (DSBs), ATR is elicited by a much broader spectrum of DNA damage and replication stress (Cimprich and Cortez 2008;Marechal and Zou 2013;Shiloh and Ziv 2013). Once activated, ATM and ATR phosphorylate and activate their effector kinases, Chk2 and Chk1, respectively. Together, the ATMChk2 and ATR-Chk1 kinase cascades phosphorylate a number of substrates involved in DNA repair, DNA replication, and cell cycle transitions, coordinating these processes to suppress genomic instability. In addition to the phosphorylation events mediated by the ATM and ATR pathways, several other types of post-translational modifications (PTMs), such as ubiquitylation, SUMOylation, methylation, acetylation, and poly-ADP ribosylation, are also implicated in the DDR (Bekker-Jensen and Mailand 2010;Huen et al. 2010;Lukas et al. 2011;Jackson and Durocher 2013). We recently found that the efficient activation of ATR relies on a ubiquitylation circuitry mediated by RPA-ssDNA (RPA-coated ssDNA) and PRP19 (Marechal et al. 2014). This new finding raises a question as to whether other PTMs also participate in DNA damage signaling through the ATR path...

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Sumoylation of MDC1 is important for proper DNA damage response

Cited by 152 publications

References 53 publications

RNF4 is required for DNA double-strand break repair in vivo

RNF4 is required for DNA double-strand break repair in vivo

RNF 4 interacts with both SUMO and nucleosomes to promote the DNA damage response

SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

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