期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 30, 页码 E6054-E6063出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1700694114
关键词
double-strand break; G9a; RPA; CK2; homologous recombination
资金
- National Key Research and Development Program of China [2013CB911000, 2017YFA0503900]
- National Natural Science Foundation of China [31570812, 81530074, 81621063, 81372165, 91319302]
- Discipline Construction Funding of Shenzhen
- Shenzhen Municipal Commission of Science and Technology Innovation [JCYJ20160427104855100]
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.
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