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.

中文翻译：

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赖氨酸甲基转移酶EHMT1和EHMT2介导的MDC1甲基化调节DNA损伤位点两侧的主动ATM积累。

翻译后修饰介导的染色质动力学在细胞对遗传毒性胁迫的反应中起着至关重要的作用，以维持基因组的完整性。MDC1是DNA损伤反应（DDR）中的关键染色质衔接子，其甲基化对于在DNA双链断裂（DSB）位点募集修复因子至关重要，但是它们的精确分子机制仍然难以捉摸。在这里，我们确定常染色体染色质组氨酸赖氨酸N-甲基转移酶1（EHMT1）和EHMT2作为MDC1的新型调节剂，这是在DSB位点积累DDR因子（例如53BP1和RAP80）所必需的。MDC1主要与EHMT1相互作用，这是由DNA损伤引发的ATM信号促成的，而EHMT2则主要调节MDC1赖氨酸45的甲基化。这种调节修饰促进了MDC1和ATM之间的相互作用，从而在受损的染色质和功能异常的端粒上扩展了活化的ATM。这些发现确定EHMT1和EHMT2为DDR成分，通过MDC1的适当动态甲基化对基因组完整性的维持具有影响。