Abstract
Upon induction of DNA breaks, ATM activation leads to a cascade of local chromatin modifications that promote efficient recruitment of DNA repair proteins. Errors in this DNA repair pathway lead to genomic instability and cancer predisposition. Here, we show that the protein lysine methyltransferase G9a (also known as EHMT2) and GLP1 (also known as EHMT1) are critical components of the DNA repair pathway. G9a and GLP1 rapidly localizes to DNA breaks, with GLP1 localization being dependent on G9a. ATM phosphorylation of G9a on serine 569 is required for its recruitment to DNA breaks. G9a catalytic activity is required for the early recruitment of DNA repair factors including 53BP and BRCA1 to DNA breaks. Inhibition of G9a catalytic activity disrupts DNA repair pathways and increases sensitivity to ionizing radiation. Thus, G9a is a potential therapeutic target in the DNA repair pathway.
Highlights
Many important biological processes are regulated by post-translational modifications
Both G9a and GLP1 are phosphorylated by ATM kinase, and catalytic inhibition of G9a leads to genomic instability[19], suggesting they play a role in the DNA damage response (DDR)[20]
10 minutes processed for IF staining using indicated antibodies. (B) HeLa cells co-transfected with GFP-G9a were micro-irradiated IF staining for H2AX and GFP signal are shown. (C) PLA was used to visualize regions of close proximity between γH2AX and either 53BP1, G9a or GLP1 in U2OS cells treated with micro-irradiation
Summary
Many important biological processes are regulated by post-translational modifications. Loss of either G9a or GLP1 in the mouse leads to embryonic lethality[17,18], demonstrating they play critical roles in development. Both G9a and GLP1 are phosphorylated by ATM kinase, and catalytic inhibition of G9a leads to genomic instability[19], suggesting they play a role in the DNA damage response (DDR)[20]. Loss of G9a or its catalytic inhibition impairs both HR and NHEJ and leads to radio-sensitivity These findings establish G9a as a potentially pharmacologically targetable component of the DNA repair pathway
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