Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 516080, China.
Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6054-E6063. doi: 10.1073/pnas.1700694114. Epub 2017 Jul 11.
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.
组蛋白甲基转移酶 G9a 在促进癌细胞生长和基因抑制方面具有关键作用，但它是否也与 DNA 损伤反应有关，很少有研究。在这里，我们报告说，G9a 的缺失会损害 DNA 损伤修复，并增强癌细胞对辐射和化疗药物的敏感性。在响应 DNA 双链断裂 (DSB) 时，G9a 被酪蛋白激酶 2 (CK2) 磷酸化丝氨酸 211 并募集到染色质上。富含染色质的 G9a 然后可以直接与复制蛋白 A (RPA) 相互作用，并促进 RPA 和 Rad51 重组酶加载到 DSB 上。这种机制促进了同源重组 (HR) 和细胞存活。我们证实了 RPA 和 G9a 之间的相互作用对于 DNA 损伤时 RPA 焦点的形成和 HR 至关重要。总之，我们的研究结果表明，基于 CK2-G9a-RPA 的调控途径允许癌细胞中的 HR，并为使用 G9a 抑制剂作为癌症治疗提供了更多的依据。
