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

Scientific Reports
Sugiko WatanabeYoshihiko Maehara

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.

References

Feb 28, 2003·Nature·Michal GoldbergStephen P Jackson
Sep 6, 2003·Current Biology : CB·Hiroyuki TakaiTitia de Lange
Oct 2, 2003·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xingzhi Xu, David F Stern
Dec 13, 2006·Genes & Development·Nadya Dimitrova, Titia de Lange
Jan 2, 2008·The Journal of Cell Biology·Stine JørgensenClaus Storgaard Sørensen
Sep 27, 2008·The EMBO Journal·Makoto TachibanaYoichi Shinkai
Apr 4, 2009·Trends in Cell Biology·Haico van Attikum, Susan M Gasser
Oct 23, 2010·Molecular Cell·Alberto Ciccia, Stephen J Elledge
Mar 3, 2011·Genes & Development·Sophie E Polo, Stephen P Jackson
Nov 19, 2013·Nature Structural & Molecular Biology·Sugiko WatanabeJiri Bartek
Sep 1, 2015·Cell·Rebecca C Burgess, Tom Misteli
Oct 7, 2015·Frontiers in Immunology·Francesco CascielloJason S Lee
Jul 13, 2017·Proceedings of the National Academy of Sciences of the United States of America·Qiaoyan YangWei-Guo Zhu
Dec 2, 2017·Scientific Reports·Vasudeva GinjalaShridar Ganesan

❮ Previous
Next ❯

Methods Mentioned

BETA
immunoprecipitation
proximity ligation assay
PCR
enzyme-linked immunosorbent assay
co-IP

Software Mentioned

ImageJ
NIS Elements
AxioVision

Related Concepts

Related Feeds

Ataxia telangiectasia

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.

Ataxia telangiectasia (MDS)

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.