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

研究成果: Article査読

91 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)103-110
ページ数8
ジャーナルJournal of Immunology
178
1
DOI
出版ステータスPublished - 2007 1 1
外部発表はい

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学

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