DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
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DOI：
10.1038/nature01368
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发表时间：
2003-01-30
期刊：
影响因子：
64.8
通讯作者：
Kastan, MB
中科院分区：
文献类型：
--
作者：
Bakkenist, CJ;Kastan, MB
ATM蛋白激酶的突变与人类疾病共济失调-毛细血管扩张有关，它在哺乳动物细胞中介导对电离辐射的反应。在这里，我们表明，在未受辐射的细胞中，ATM作为二聚体或更高阶多聚体保持不活跃，其激酶结构域与丝氨酸1981周围的区域结合，该区域包含在先前描述的“脂肪”结构域中。细胞辐射诱导丝氨酸1981的快速分子间自动磷酸化，导致二聚体解离并启动细胞ATM激酶活性。细胞中的大多数ATM分子在低剂量的辐射后迅速在这个部位被磷酸化，并且在细胞中仅引入几个DNA双链断裂后就可以检测到磷酸特异性抗体的结合。ATM激酶的激活似乎是细胞对辐射反应的启动事件，我们的数据表明ATM的激活不依赖于与DNA链断裂的直接结合，而可能是染色质结构变化的结果。
The ATM protein kinase, mutations of which are associated with the human disease ataxia-telangiectasia, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described 'FAT' domain. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation, and our data indicate that ATM activation is not dependent on direct binding to DNA strand breaks, but may result from changes in the structure of chromatin.