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Regulation of Reactive Oxygen Species by Atm Is Essential for Proper Response to DNA Double-Strand Breaks in Lymphocytes¹

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^2,* and Atsushi Hirao^2,,||

^* Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan; Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Laboratory of Tumor Biology, Department of Medical Genome Sciences, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan; Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; ^¶ The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario, Canada; and ^|| Core Research for Evolutional Science, and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

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^–/– mouse 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Grant-in-Aid for Young Scientists from the Ministry of Education, Science, Sports, and Culture, Japan (to K.I.), and Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Science, Sports, and Culture, Japan (to T.S.).

² Address correspondence and reprint requests to Dr. Atsusi Hirao, Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, 920-0934, Japan; E-mail address: ahirao{at}kenroku.kanazawa-u.ac.jp or Dr. Toshio Suda, Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo 160-8582, Japan; E-mail address: sudato{at}sc.itc.keio.ac.jp

³ Abbreviations used in this paper: A-T, ataxia telangiectasia; ATM, A-T mutated; IR, ionizing radiation; NHEJ, nonhomologous end-joining; DSB, double-strand break; ROS, reactive oxygen species; NAC, N-acetyl-L-cysteine; Tempol, 4-hydroxytetramethy-L-piperidine-1-oxyl; CSR, class switch recombination; MEF, murine embryonic fibroblast; DC-PCR, digestion-circularization-PCR; nAChR, nicotinic acetylcholine receptor; DCF-DA, 2'-7'-dichlorofluorescene diacetate; WT, wild type; SA--gal, senescence-associated -galactosidase; GSH, glutathione; SOD, superoxide dismutase.

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