Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway
Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway
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DOI：
10.1101/gad.1200304
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发表时间：
2004-06-15
影响因子：
10.5
通讯作者：
Kastan, MB
中科院分区：
文献类型：
--
作者：
Kitagawa, R;Bakkenist, CJ;Kastan, MB
ATM蛋白激酶通过分子间自磷酸化响应DNA损伤而被激活，并启动促进细胞存活和减少染色体断裂的细胞信号传导途径。在这里，我们表明，NBS1和BRCA1的招聘之前激活的ATM的电离辐射后的DNA断裂的网站所需的，这种招聘是需要的SMC 1的磷酸化ATM。为了探索SMC 1磷酸化的功能重要性，产生了鼠细胞，其中SMC 1中的两个损伤诱导的磷酸化位点发生突变。尽管这些细胞在IR后表现出ATM、NBS1和BRCA1蛋白的正常磷酸化和病灶形成，但它们在DNA损伤后表现出缺陷的S期检查点、存活率降低和染色体畸变增加。这些观察结果表明，在缺乏ATM，NBS1或BRCA 1的细胞中观察到的许多异常应激反应是由于ATM迁移到DNA断裂位点的失败以及由此导致的SMC 1磷酸化的缺乏。
The ATM protein kinase is activated by intermolecular autophosphorylation in response to DNA damage and initiates cellular signaling pathways that facilitate cell survival and reduce chromosomal breakage. Here, we show that NBS1 and BRCA1 are required for the recruitment of previously activated ATM to the sites of DNA breaks after ionizing irradiation, and that this recruitment is required for the phosphorylation of SMC1 by ATM. To explore the functional importance of SMC1 phosphorylation, murine cells were generated, in which the two damage-induced phosphorylation sites in SMC1 are mutated. Although these cells demonstrate normal phosphorylation and focus formation of ATM, NBS1, and BRCA1 proteins after IR, they exhibit a defective S-phase checkpoint, decreased survival, and increased chromosomal aberrations after DNA damage. These observations suggest that many of the abnormal stress responses seen in cells lacking ATM, NBS1, or BRCA1 result from a failure of ATM migration to sites of DNA breaks and a resultant lack of SMC1 phosphorylation.