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

Qiaoyan Yang1, Qian Zhu1, Xiaopeng Lu1,2

  • 1Key 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.

Proceedings of the National Academy of Sciences of the United States of America
|July 13, 2017
PubMed

Insights

Histone methyltransferase G9a aids cancer cell survival by facilitating DNA repair. Its inhibition impairs DNA damage response, increasing cancer cell sensitivity to therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • DNA Repair Mechanisms

Background:

  • Histone methyltransferase G9a (G9a) is known for its roles in cancer cell growth and gene suppression.
  • Its involvement in the DNA damage response (DDR) remains largely unexplored.

Purpose of the Study:

  • To investigate the role of G9a in the DNA damage response and its potential as a therapeutic target in cancer.

Main Methods:

  • Studied the effect of G9a loss on DNA damage repair and sensitivity to genotoxic agents.
  • Investigated G9a phosphorylation, recruitment to chromatin, and interaction with DNA repair proteins like Replication Protein A (RPA) following DNA double-strand breaks (DSBs).
  • Assessed the impact of G9a-RPA interaction on RPA foci formation and homologous recombination (HR).

Main Results:

  • Loss of G9a impairs DNA damage repair and increases cancer cell sensitivity to radiation and chemotherapy.
  • G9a is phosphorylated by casein kinase 2 (CK2) at serine 211 in response to DSBs and recruited to chromatin.
  • Chromatin-bound G9a directly interacts with RPA, promoting RPA and Rad51 loading to DSBs, which facilitates HR and cell survival.

Conclusions:

  • A novel regulatory pathway involving CK2-G9a-RPA in facilitating homologous recombination in cancer cells was identified.
  • G9a plays a critical role in DNA double-strand break repair through homologous recombination.
  • Targeting G9a may represent a viable therapeutic strategy to enhance cancer treatment efficacy.
Keywords:
CK2G9aRPAdouble-strand breakhomologous recombination

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