Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks
Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks
复制标题
DOI：
10.1126/science.286.5442.1162
复制
发表时间：
1999-11-05
期刊：
影响因子：
56.9
通讯作者：
Elledge, SJ
中科院分区：
文献类型：
--
作者：
Cortez, D;Wang, Y;Elledge, SJ
Brca 1（乳腺癌基因1）肿瘤抑制蛋白在响应DNA损伤时被磷酸化，本研究的结果表明，检查点蛋白激酶ATM（在共济失调毛细血管扩张症中突变）是响应电离辐射的Brca 1磷酸化所必需的。ATM驻留在一个复杂的Brca 1和磷酸化的Brca 1在体内和体外的一个区域，包含集群的丝氨酸-谷氨酰胺残基。这个结构域的磷酸化似乎在功能上是重要的，因为突变的Brca 1蛋白缺乏两个磷酸化sires未能挽救Brca 1缺陷细胞系的辐射超敏反应。因此，检查点激酶ATM对Brca 1的磷酸化可能对DNA双链断裂的正确反应至关重要，并可能为ATM在乳腺癌中的作用提供分子解释。
The Brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to DNA damage, Results from this study indicate that the checkpoint protein kinase ATM (mutated in ataxia telangiectasia) was required for phosphorylation of Brca1 in response to ionizing radiation. ATM resides in a complex with Brca1 and phosphorylated Brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated Brca1 protein lacking two phosphorylation sires failed to rescue the radiation hypersensitivity of a Brca1-deficient cell line. Thus, phosphorylation of Brca1 by the checkpoint kinase ATM may be critical for proper responses to DNA double-strand breaks and may provide a molecular explanation far the role of ATM in breast cancer.