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

被引：18
作者：
Watanabe, Sugiko [1 ,2 ]
Iimori, Makoto [1 ,3 ]
Chan, David Virya [2 ]
Hara, Eiji [2 ]
Kitao, Hiroyuki [1 ,3 ]
Maehara, Yoshihiko [1 ,4 ]
机构：
[1] Kyushu Univ, Innovat Anticanc Strategy Therapeut & Diag Grp, Innovat Ctr Med Redox Nav, Fukuoka, Fukuoka 8128582, Japan
[2] Osaka Univ, Microbial Dis Res Inst, Dept Mol Microbiol, Suita, Osaka 5650871, Japan
[3] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Mol Canc Biol, Fukuoka, Fukuoka 8128582, Japan
[4] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka, Fukuoka 8128582, Japan
来源：
SCIENTIFIC REPORTS | 2018年 / 8卷
关键词：
HISTONE METHYLTRANSFERASES; CHROMATIN RESPONSE; FOCUS; G9A; DEGRADATION; COMPLEXES; H3K9; SET8; GLP;
D O I：
10.1038/s41598-018-29239-3
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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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页数：10
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