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ATM-mediated KDM2A phosphorylation is required for the DNA damage repair

L-L Cao1, F Wei1, Y Du1

  • 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, 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, China.

Oncogene
|March 31, 2015
PubMed

Insights

The ataxia-telangiectasia mutated (ATM) protein regulates DNA repair by phosphorylating KDM2A, a histone demethylase. This phosphorylation enhances DNA repair efficiency and cell survival following DNA damage.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • The DNA damage response is crucial for maintaining genomic stability.
  • The precise mechanisms by which ATM protein regulates DNA repair are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which ATM regulates DNA damage repair.
  • To investigate the role of KDM2A in the ATM-mediated DNA damage response.

Main Methods:

  • Co-immunoprecipitation assays to study ATM-KDM2A interaction.
  • Site-directed mutagenesis and mass spectrometry to identify phosphorylation sites.
  • Chromatin immunoprecipitation to assess histone modifications and binding.
  • Cell viability assays to evaluate cell survival.

Main Results:

  • ATM interacts with KDM2A, with increased interaction upon DNA double-strand breaks.
  • ATM phosphorylates KDM2A at Threonine 632 (T632) in response to DNA damage.
  • Phosphorylation of KDM2A at T632 reduces its chromatin binding, leading to increased H3K36 dimethylation near damage sites.
  • Enriched H3K36 dimethylation recruits the MRE11 complex via NBS1, promoting DNA repair and cell survival.

Conclusions:

  • ATM-mediated phosphorylation of KDM2A is a novel mechanism linking histone modification to DNA damage response.
  • This pathway involving KDM2A, H3K36 dimethylation, and the MRE11 complex is critical for efficient DNA repair and cell survival.

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