Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes
Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes
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DOI：
10.4049/jimmunol.178.1.103
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
--
作者：
Ito, Keisuke;Takubo, Keiyo;Hirao, Atsushi
共济失调毛细血管扩张突变(ATM)基因在维持基因组稳定性中起着关键作用。尽管最近有研究表明抗氧化剂能抑制ATM(-/-)小鼠的淋巴肿大，但其机制仍不清楚。在这项研究中，我们深入研究了活性氧物种(ROS)在ATM(-/-)小鼠表型中的作用。抗氧化剂N-乙酰-L-半胱氨酸降低ROS可防止ATM(-/-)小鼠胚胎成纤维细胞衰老表型的出现、对全身照射的超敏反应和ATM(-/-)小鼠胸腺淋巴瘤的发生。为了了解防止淋巴瘤发生的机制，我们分析了ATM(-/-)小鼠肿瘤前淋巴细胞的发育。NAC可减轻ATM(-/-)小鼠Ig类开关重组的损伤，表明ROS升高导致体内对程序性双链断裂的异常反应。值得注意的是，给ATM(-/-)小鼠体内注射NAC恢复了正常的T细胞发育，并抑制了V(D)J的异常重组。我们得出结论，ATM介导的ROS调节对于正确的DNA重组、预防免疫缺陷和淋巴肿大是必不可少的。
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.