Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, 195 Little Albany street, New Brunswick, New Jersey, 08903, USA.
Cornell University, College of Engineering, Department of Biological Engineering, 111 Wing Drive, Ithaca, NY, 14853-5701, USA.
Sci Rep. 2017 Nov 30;7(1):16613. doi: 10.1038/s41598-017-16480-5.
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.
在诱导 DNA 断裂后，ATM 的激活导致一系列局部染色质修饰，促进了 DNA 修复蛋白的有效招募。该 DNA 修复途径中的错误会导致基因组不稳定和癌症易感性。在这里，我们表明蛋白赖氨酸甲基转移酶 G9a（也称为 EHMT2）和 GLP1（也称为 EHMT1）是 DNA 修复途径的关键组成部分。G9a 和 GLP1 迅速定位于 DNA 断裂处，GLP1 的定位依赖于 G9a。ATM 对 G9a 丝氨酸 569 的磷酸化是其招募到 DNA 断裂处所必需的。G9a 的催化活性对于包括 53BP 和 BRCA1 在内的 DNA 修复因子的早期招募是必需的。抑制 G9a 的催化活性会破坏 DNA 修复途径，并增加对电离辐射的敏感性。因此，G9a 是 DNA 修复途径中的一个潜在治疗靶点。
