SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint
SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint
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DOI：
10.1101/gad.970702
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发表时间：
2002-03-01
影响因子：
10.5
通讯作者：
Qin, J
中科院分区：
文献类型：
--
作者：
Yazdi, PT;Wang, Y;Qin, J
染色体结构维持蛋白（SMC）（SMC 1、SMC 3）是进化上保守的染色体蛋白，是姐妹染色单体凝聚所必需的凝聚素复合体的组成部分。这些蛋白质也可以在DNA修复中发挥作用。在这里，我们报告说，SMC 1是DNA损伤反应网络的一个组成部分，作为一个效应器在ATM/NBS 1依赖的S期检查点途径。SMC 1与BRCA 1结合，并以ATM和NBS 1依赖性方式对IR作出反应而磷酸化。使用质谱，我们确定ATM在体内磷酸化SMC 1的S957和S966。SMC 1的S957和/或S966的磷酸化是响应IR激活S期检查点所必需的。我们还发现，ATM对NBS 1的磷酸化是SMC 1磷酸化所必需的，从而确立了NBS 1在ATM/NBS 1/SMC 1通路中作为适配器的作用。ATM/CHK 2/CDC 25 A通路也参与S期检查点激活，但该通路在NBS细胞中是完整的。我们的研究结果表明，ATM/NBS 1/SMC 1通路是S期检查点通路的一个独立分支，不同于ATM/CHK 2/CDC 25 A分支。因此，本研究建立了ATM/NBS 1/SMC 1分支，为NBS细胞S期检查点缺陷提供了分子基础。
Structural maintenance of chromosomes (SMC) proteins (SMC1, SMC3) are evolutionarily conserved chromosomal proteins that are components of the cohesin complex, necessary for sister chromatid cohesion. These proteins may also function in DNA repair. Here we report that SMC1 is a component of the DNA damage response network that functions as an effector in the ATM/NBS1-dependent S-phase checkpoint pathway. SMC1 associates with BRCA1 and is phosphorylated in response to IR in an ATM- and NBS1-dependent manner. Using mass spectrometry, we established that ATM phosphorylates S957 and S966 of SMC1 in vivo. Phosphorylation of S957 and/or S966 of SMC1 is required for activation of the S-phase checkpoint in response to IR. We also discovered that the phosphorylation of NBS1 by ATM is required for the phosphorylation of SMC1, establishing the role of NBS1 as an adaptor in the ATM/NBS1/SMC1 pathway. The ATM/CHK2/CDC25A pathway is also involved in the S-phase checkpoint activation, but this pathway is intact in NBS cells. Our results indicate that the ATM/NBS1/SMC1 pathway is a separate branch of the S-phase checkpoint pathway, distinct from the ATM/CHK2/CDC25A branch. Therefore, this work establishes the ATM/NBS1/SMC1 branch, and provides a molecular basis for the S-phase checkpoint defect in NBS cells.