G9a coordinates with the RPA complex to promote DNA damage repair and cell survival

Yang, Qiong; Zhu, Qian; Lu, Xiaopeng; Du, Yipeng; Cao, Linlin; Shen, Chen; Hou, Tianyun; Li, Meiting; Li, Zhiming; Liu, Chaohua; Wu, Di; Xu, Xingzhi; Wang, Lina; Wang, Haiying; Zhao, Ying; Yang, Yang; Zhu, Weiguo

doi:10.1073/pnas.1700694114

Cited by 72 publications

(58 citation statements)

References 68 publications

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“…The WIZ interacting partner G9a has been reported to directly interact with and is crucial for chromatin recruitment of RPA to damage sites ( Yang et al, 2017 ), which activates the ATR-CHK1 axis of DNA damage response. We examined the sensitivity of WIZ-KO cells with hydroxyurea (HU), ATR inhibitor (ATRi; AZD6738), CHK1 inhibitor (CHKi; LY2606368), and PARP inhibitor (PARPi; olaparib) ( Figures S6E-S6H ).…”

Section: Resultsmentioning

confidence: 99%

Replisome Dynamics and Their Functional Relevance upon DNA Damage through the PCNA Interactome

et al. 2018

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SUMMARY Eukaryotic cells use copious measures to ensure accurate duplication of the genome. Various genotoxic agents pose threats to the ongoing replication fork that, if not efficiently dealt with, can result in replication fork collapse. It is unknown how replication fork is precisely controlled and regulated under different conditions. Here, we examined the complexity of replication fork composition upon DNA damage by using a PCNA-based proteomic screen to uncover known and unexplored players involved in replication and replication stress response. We used camptothecin or UV radiation, which lead to fork-blocking lesions, to establish a comprehensive proteomics map of the replisome under such replication stress conditions. We identified and examined two potential candidate proteins WIZ and SALL1 for their roles in DNA replication and replication stress response. In addition, our unbiased screen uncovered many prospective candidate proteins that help fill the knowledge gap in understanding chromosomal DNA replication and DNA repair.

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Section: Resultsmentioning

confidence: 99%

Replisome Dynamics and Their Functional Relevance upon DNA Damage through the PCNA Interactome

et al. 2018

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“…Laser micro-irradiation was performed as previously descried. 63 Briefly, cells were grown on a glass-bottomed dish and locally irradiated with a 365 nm pulsed nitrogen UV laser (16 Hz pulse, 41% laser output) generated from a micropoint system (Andor). This system was directly coupled to the epifluorescence path of the Nikon A1 confocal imaging system and time-lapse images were captured every 10 s for the indicated time.…”

Section: Methodsmentioning

confidence: 99%

Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair

Tang

et al. 2018

Cell Res

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Linker histone H1 is a master regulator of higher order chromatin structure, but its involvement in the DNA damage response and repair is unclear. Here, we report that linker histone H1.2 is an essential regulator of ataxia telangiectasia mutated (ATM) activation. We show that H1.2 protects chromatin from aberrant ATM activation through direct interaction with the ATM HEAT repeat domain and inhibition of MRE11-RAD50-NBS1 (MRN) complex-dependent ATM recruitment. Upon DNA damage, H1.2 undergoes rapid PARP1-dependent chromatin dissociation through poly-ADP-ribosylation (PARylation) of its C terminus and further proteasomal degradation. Inhibition of H1.2 displacement by PARP1 depletion or an H1.2 PARylation-dead mutation compromises ATM activation and DNA damage repair, thus leading to impaired cell survival. Taken together, our findings suggest that linker histone H1.2 functions as a physiological barrier for ATM to target the chromatin, and PARylation-mediated active H1.2 turnover is required for robust ATM activation and DNA damage repair.

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“…In this study, among the candidate lysine methyltransferases regulating MDC1 in DDR, EHMT1 [also known as G9A-like protein; GLP or KMT1D (lysine methyltransferase 1D)] and EHMT2 [also known as G9A or KMT1C (lysine methyltransferase 1C)] were identified as mediators for the proper methylation of MDC1. Interestingly, recent studies have shown that EHMT2 7 and its catalytic activity 8 , 9 promote DNA repair in response to DSB-inducing genotoxic stress. However, the precise mechanism of EHMT2 linked to EHMT1 in DDR remain elusive.…”

Section: Introductionmentioning

confidence: 99%

MDC1 methylation mediated by lysine methyltransferases EHMT1 and EHMT2 regulates active ATM accumulation flanking DNA damage sites

Watanabe

Iimori

Chan

et al. 2018

Sci Rep

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Chromatin dynamics mediated by post-translational modifications play a crucial role in cellular response to genotoxic stress for the maintenance of genome integrity. MDC1 is a pivotal chromatin adaptor in DNA damage response (DDR) and its methylation is essential to recruit repair factors at DNA double-strand break (DSB) sites, yet their precise molecular mechanisms remain elusive. Here we identified euchromatic histone-lysine N-methyltransferase 1 (EHMT1) and EHMT2 as novel regulators of MDC1, which is required for the accumulation of DDR factors e.g. 53BP1 and RAP80, at the DSB sites. MDC1 interacts mainly with EHMT1, which is facilitated by DNA damage-initiated ATM signalling, and EHMT2 dominantly modulates methylation of MDC1 lysine 45. This regulatory modification promotes the interaction between MDC1 and ATM to expand activated ATM on damaged chromatin and dysfunctional telomere. These findings identify EHMT1 and EHMT2 as DDR components, with implications for genome-integrity maintenance through proper dynamic methylation of MDC1.

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G9a coordinates with the RPA complex to promote DNA damage repair and cell survival

Cited by 72 publications

References 68 publications

Replisome Dynamics and Their Functional Relevance upon DNA Damage through the PCNA Interactome

Replisome Dynamics and Their Functional Relevance upon DNA Damage through the PCNA Interactome

Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair

MDC1 methylation mediated by lysine methyltransferases EHMT1 and EHMT2 regulates active ATM accumulation flanking DNA damage sites

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