Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes

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.