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

Sugiko Watanabe,Eiji Hara,Hiroyuki Kitao,David Virya Chan,Yoshihiko Maehara,Makoto Iimori

doi:10.1038/s41598-018-29239-3

Sugiko Watanabe, Eiji Hara + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-29239-3

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Journal: Scientific Reports	Publication Date: Jul 18, 2018
Citations: 16	License type: open-access

Affiliation: Kyushu University, Osaka University

Abstract

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.

Highlights

Cells are constantly assaulted by intrinsic and environmental factors that can induce genotoxic insults[1,2]
Depletion of euchromatic histone-lysine N-methyltransferase 1 (EHMT1) or EHMT2 had little effect on mediator of DNA damage checkpoint 1 (MDC1) recruitment to damaged chromatin, but it had markedly reduced the accumulation of downstream factors of MDC1 in DNA damage response (DDR) (Figs S1a and S2a)
The EHMT2 in EHMT1/EHMT2 heterodimer methylates MDC1 to amplify the local activation of ATM to expand the phosphor-signal around the damaged chromatin (Fig. 5)

Summary

Introduction

Cells are constantly assaulted by intrinsic (e.g. reactive oxygen species) and environmental (e.g. ultraviolet light, ionizing radiation, chemical agents) factors that can induce genotoxic insults[1,2]. To counteract the threats to genome integrity, cells have evolved a sophisticated mechanisms of DNA damage responses (DDR) and associated downstream repair pathways. We show that EHMT1 and EHMT2-dependent methylation of MDC1 is required for the interaction between activated ATM and MDC1 to amplify the DDR signal, followed by recruitment of repair factors to DNA damage sites including the dysfunctional telomere. These data enhance our understanding of EHMT1 and EHMT2 as DDR components, through proper dynamic methylation of MDC1 to maintain genome integrity

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