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

Keisuke Ito, Keiyo Takubo, Fumio Arai, Hitoshi Satoh, Sahoko Matsuoka, Masako Ohmura, Kazuhito Naka, Masaki Azuma, Kana Miyamoto, Kentaro Hosokawa, Yasuo Ikeda, Tak W. Mak, Toshio Suda, Atsushi Hirao

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

The ataxia telangiectasia-mutated (ATM) gene plays a pivotal role in the maintenance of genomic stability. Although it has been recently shown that antioxidative agents inhibited lymphomagenesis in Atm-/- mice, the mechanisms remain unclear. In this study, we intensively investigated the roles of reactive oxygen species (ROS) in phenotypes of Atm-/- mice. Reduction of ROS by the antioxidant N-acetyl-L-cysteine (NAC) prevented the emergence of senescent phenotypes in Atm-/- moose embryonic fibroblasts, hypersensitivity to total body irradiation, and thymic lymphomagenesis in Atm-/- mice. To understand the mechanisms for prevention of lymphomagenesis, we analyzed development of pretumor lymphocytes in Atm-/- mice. Impairment of Ig class switch recombination seen in Atm-/- mice was mitigated by NAC, indicating that ROS elevation leads to abnormal response to programmed double-strand breaks in vivo. Significantly, in vivo administration of NAC to Atm-/- mice restored normal T cell development and inhibited aberrant V(D)J recombination. We conclude that Atm-mediated ROS regulation is essential for proper DNA recombination, preventing immunodeficiency, and lymphomagenesis.

Original languageEnglish (US)
Pages (from-to)103-110
Number of pages8
JournalJournal of Immunology
Volume178
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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