The ATM Cofactor ATMIN Protects against Oxidative Stress and Accumulation of DNA Damage in the Aging Brain
The ATM Cofactor ATMIN Protects against Oxidative Stress and Accumulation of DNA Damage in the Aging Brain
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DOI：
10.1074/jbc.m110.145896
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发表时间：
2010-12-03
影响因子：
4.8
通讯作者：
Behrens, Axel
中科院分区：
文献类型：
--
作者：
Kanu, Nnennaya;Penicud, Kay;Behrens, Axel
DNA 损伤的逐渐积累与细胞衰老和机体衰老有关。 DNA 损伤激酶 ATM 在维持基因组稳定性方面发挥着核心作用。 ATM 突变导致遗传性疾病共济失调性毛细血管扩张，其主要特征是进行性神经变性和癌症易感性。尽管 ATM 功能在防止 DNA 氧化损伤和衰老过程中的重要性已得到充分描述，但这些刺激激活 ATM 的机制尚不清楚。在这里，我们将 ATM 相互作用蛋白 (ATMIN) 确定为响应氧化应激和衰老的 ATM 信号通路的重要组成部分。缺乏 ATMIN (atmin(Delta/Delta)) 的胚胎在子宫内死亡，并且磷酸化组蛋白 H2aX 阳性细胞数量增加，表明 DNA 损伤增加。 atmin(Delta/Delta) 小鼠胚胎成纤维细胞在大气氧水平 (20%) 下培养时，会积累 DNA 损伤并过早进入衰老状态，但通过添加抗氧化剂以及在生理氧水平 (3%) 下培养细胞，可以挽救这种缺陷。为了应对急性氧化应激，atmin(Delta/Delta) 小鼠胚胎成纤维细胞表现出稍低水平的 ATM 磷酸化和减少的 ATM 底物磷酸化。在小鼠神经系统中条件性删除 ATMIN (atmin(Delta N)) 会导致多巴胺能神经元数量减少，ATM 缺陷也是如此。在老年对照小鼠中观察到了 ATM 活性，但在年轻对照小鼠中未观察到，但衰老诱导的 ATM 信号传导因 ATMIN 缺乏而受损。因此，老年atmin(Delta N)小鼠的皮质中DNA损伤不断累积，并伴有神经胶质增生，导致衰老突变小鼠的死亡率增加。这些结果表明 ATMIN 通过氧化应激介导 ATM 激活，从而 ATMIN 通过防止 DNA 损伤的累积来保护衰老的大脑。
Progressive accumulation of DNA damage is causally involved in cellular senescence and organismal aging. The DNA damage kinase ATM plays a central role in maintaining genomic stability. ATM mutations cause the genetic disorder ataxia telangiectasia, which is primarily characterized by progressive neurodegeneration and cancer susceptibility. Although the importance of ATM function to protect against oxidative DNA damage and during aging is well described, the mechanism of ATM activation by these stimuli is not known. Here we identify ATM interactor (ATMIN) as an essential component of the ATM signaling pathway in response to oxidative stress and aging. Embryos lacking ATMIN (atmin(Delta/Delta)) died in utero and showed increased numbers of cells positive for phosphorylated histone H2aX, indicative of increased DNA damage. atmin(Delta/Delta) mouse embryonic fibroblasts accumulated DNA damage and prematurely entered senescence when cultured at atmospheric oxygen levels (20%), but this defect was rescued by addition of an antioxidant and also by culturing cells at physiological oxygen levels (3%). In response to acute oxidative stress, atmin(Delta/Delta) mouse embryonic fibroblasts showed slightly lower levels of ATM phosphorylation and reduced ATM substrate phosphorylation. Conditional deletion of ATMIN in the murine nervous system (atmin(Delta N)) resulted in reduced numbers of dopaminergic neurons, as does ATM deficiency. ATM activity was observed in old, but not in young, control mice, but aging-induced ATM signaling was impaired by ATMIN deficiency. Consequently, old atmin(Delta N) mice showed accumulation of DNA damage in the cortex accompanied by gliosis, resulting in increased mortality of aging mutant mice. These results suggest that ATMIN mediates ATM activation by oxidative stress, and thereby ATMIN protects the aging brain by preventing accumulation of DNA damage.