G9a coordinates with the RPA complex to promote DNA damage repair and cell survival

被引：67

作者：

Yang, Qiaoyan ^{[1
]}

Zhu, Qian ^{[1
]}

Lu, Xiaopeng ^{[1
,2
]}

Du, Yipeng ^{[1
]}

Cao, Linlin ^{[1
]}

Shen, Changchun ^{[1
]}

Hou, Tianyun ^{[1
,2
]}

Li, Meiting ^{[1
]}

Li, Zhiming ^{[1
,2
]}

Liu, Chaohua ^{[1
]}

Wu, Di ^{[1
]}

Xu, Xingzhi ^{[2
]}

Wang, Lina ^{[1
]}

Wang, Haiying ^{[1
]}

Zhao, Ying ^{[1
]}

Yang, Yang ^{[1
]}

Zhu, Wei-Guo ^{[1
,2
]}

机构：

[1] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci,Key Lab Carcinogenesis & Transl, Dept Biochem & Mol Biol,Minist Educ,Beijing Key L, Beijing 100191, Peoples R China

[2] Shenzhen Univ, Sch Med, Dept Biochem & Mol Biol, Guangdong Key Lab Genome Stabil & Human Dis Preve, Shenzhen 516080, Peoples R China

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 30期

基金：

中国国家自然科学基金;

关键词：

double-strand break; G9a; RPA; CK2; homologous recombination; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION REPAIR; REPLICATION PROTEIN-A; HISTONE H3; METHYLTRANSFERASE G9A; LYSINE-9; METHYLATION; GENOME STABILITY; DIRECTED REPAIR; DOWN-REGULATION; END RESECTION;

D O I：

10.1073/pnas.1700694114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then directly interact with replication protein A (RPA) and promote loading of the RPA and Rad51 recombinase to DSBs. This mechanism facilitates homologous recombination (HR) and cell survival. We confirmed the interaction between RPA and G9a to be critical for RPA foci formation and HR upon DNA damage. Collectively, our findings demonstrate a regulatory pathway based on CK2-G9a-RPA that permits HR in cancer cells and provide further rationale for the use of G9a inhibitors as a cancer therapeutic.

引用

页码：E6054 / E6063

页数：10

共 67 条

[1] G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status [J].