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Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in

Keisuke Ito1, Keiyo Takubo, Fumio Arai

  • 1Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan.

Journal of Immunology (Baltimore, Md. : 1950)
|December 22, 2006
PubMed

Insights

Antioxidant N-acetyl-l-cysteine (NAC) prevents genomic instability and thymic lymphomagenesis in Atm(-/-) mice by reducing reactive oxygen species (ROS). This study reveals ROS elevation drives DNA recombination defects and immunodeficiency in these mice.

Area of Science:

  • Genetics
  • Immunology
  • Molecular Biology

Background:

  • The ataxia telangiectasia-mutated (ATM) gene is crucial for genomic stability.
  • Mechanisms by which antioxidants inhibit lymphomagenesis in Atm(-/-) mice are unclear.
  • Reactive oxygen species (ROS) are implicated in Atm(-/-) mouse phenotypes.

Purpose of the Study:

  • To investigate the role of ROS in Atm(-/-) mouse phenotypes.
  • To elucidate the mechanisms of antioxidant-mediated prevention of lymphomagenesis.
  • To determine the impact of ROS on DNA recombination and immune cell development in Atm(-/-) mice.

Main Methods:

  • Treatment of Atm(-/-) mouse embryonic fibroblasts and mice with N-acetyl-l-cysteine (NAC).
  • Assessment of senescent phenotypes, irradiation hypersensitivity, and thymic lymphomagenesis.
  • Analysis of Ig class switch recombination, T cell development, and V(D)J recombination in vivo.

Main Results:

  • NAC reduced ROS, preventing senescence, irradiation hypersensitivity, and thymic lymphomagenesis in Atm(-/-) mice.
  • NAC mitigated impaired Ig class switch recombination, indicating ROS elevation causes abnormal DNA double-strand break responses.
  • In vivo NAC administration restored normal T cell development and inhibited aberrant V(D)J recombination.

Conclusions:

  • ATM-mediated ROS regulation is essential for DNA recombination.
  • Reducing ROS prevents immunodeficiency and lymphomagenesis in Atm(-/-) mice.
  • Targeting ROS offers a therapeutic strategy for ATM-related disorders.

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