Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes.
J Immunol
; 178(1): 103-10, 2007 Jan 01.
Article
in En
| MEDLINE
| ID: mdl-17182545
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
/
Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor
/
Reactive Oxygen Species
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Protein Serine-Threonine Kinases
/
Cell Cycle Proteins
/
Tumor Suppressor Proteins
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DNA-Binding Proteins
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DNA Breaks, Double-Stranded
/
Lymphoma
Limits:
Animals
Language:
En
Journal:
J Immunol
Year:
2007
Document type:
Article
Affiliation country:
Japan