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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Animals
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Antioxidants / pharmacology
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Ataxia Telangiectasia Mutated Proteins
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cellular Senescence / drug effects
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Cellular Senescence / genetics
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Cellular Senescence / immunology
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DNA Breaks, Double-Stranded*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Gene Rearrangement, beta-Chain T-Cell Antigen Receptor* / drug effects
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Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor* / drug effects
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Immunoglobulin Class Switching / drug effects
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Immunoglobulin Class Switching / genetics
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Lymphoma / genetics*
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Lymphoma / immunology
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Lymphoma / prevention & control
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Mice
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Mice, Mutant Strains
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Radiation Tolerance / drug effects
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism*
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
Substances
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Antioxidants
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Cell Cycle Proteins
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DNA-Binding Proteins
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Reactive Oxygen Species
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Tumor Suppressor Proteins
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Acetylcysteine