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Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

Kenta Yamamoto1, Yunyue Wang, Wenxia Jiang

  • 1Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.

The Journal of Cell Biology
|August 8, 2012
PubMed

Insights

The Ataxia telangiectasia mutated (ATM) kinase is crucial for embryonic development. Even catalytically inactive ATM protein plays a vital role in DNA repair and preventing genomic instability.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Ataxia telangiectasia (A-T) mutated (ATM) kinase is central to DNA damage response pathways.
  • ATM-deficient individuals and models show developmental issues and DNA repair defects.

Purpose of the Study:

  • To investigate the role of ATM kinase activity in embryonic development and DNA repair.
  • To analyze the impact of kinase-dead ATM mutations on cellular and developmental processes.

Main Methods:

  • Generation and analysis of mice with homozygous kinase-dead mutations in Atm (Atm(KD/KD)).
  • Assessment of cell proliferation, genomic instability (chromatid breaks), and DNA recombination events in Atm(KD/-) cells and lymphocytes.

Main Results:

  • Atm(KD/KD) mice exhibited embryonic lethality.
  • Atm(KD/-) cells showed proliferation defects and increased genomic instability compared to Atm(-/-) cells.
  • Despite instability, Atm(KD/-) lymphocytes maintained V(D)J and Ig class switch recombination comparable to Atm(-/-) lymphocytes.

Conclusions:

  • ATM kinase activity is essential for normal embryogenesis.
  • Catalytically inactive ATM protein retains significant functions in DNA repair processes, particularly in lymphocyte development.

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