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

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.