title: Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes.
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(-/-) 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.
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Fumio
authors.initials: F
authors.lastname: Arai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Satoh
authors.forename: Sahoko
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Masako
authors.initials: M
authors.lastname: Ohmura
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: Masaki
authors.initials: M
authors.lastname: Azuma
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hosokawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000187:drug effects; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor / Q000187:drug effects; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011836:Radiation Tolerance / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000111:Acetylcysteine