Control of the DNA damage checkpoint by Chk1 and Rad53 protein kinases through distinct mechanisms
Control of the DNA damage checkpoint by Chk1 and Rad53 protein kinases through distinct mechanisms
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DOI：
10.1126/science.286.5442.1166
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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：
Sanchez, Y;Bachant, J;Elledge, SJ
作为对DNA损伤的反应，细胞激活检查点通路，阻止细胞周期进展。在分裂酵母和哺乳动物中，对DNA损伤的有丝分裂抑制需要抑制CDK的磷酸化，由Chk1调节。这项研究表明，Chk1是酿酒酵母DNA损伤检查点功能所必需的，但它通过一个独特的机制维持后期抑制物Pds1的丰度。与其他检查点突变体不同，Chk1突变体对DNA损伤只有轻度敏感，这表明除了细胞周期停滞外，检查点功能还会影响损伤敏感性。另一种激酶Rad53既能维持细胞周期蛋白依赖性激酶1，CDK1(CDC28)的活性，又能阻止检验点激活后的后期进入。有证据表明，Rad53通过调节Polo激酶CDC5在检查点控制中发挥作用。这些结果支持一个模型，在该模型中，Chk1和Rad53分别通过Pds1和CDc5并行发挥作用，以防止DNA损伤后的后期进入和有丝分裂退出。该模型为CDC5在DNA损伤检查点适应中的作用提供了可能的解释。
In response to DNA damage, cells activate checkpoint pathways that prevent cell cycle progression. In fission yeast and mammals, mitotic arrest in response to DNA damage requires inhibitory Cdk phosphorylation regulated by Chk1. This study indicates that Chk1 is required for function of the DNA damage checkpoint in Saccharomyces cerevisiae but acts through a distinct mechanism maintaining the abundance of Pds1, an anaphase inhibitor. Unlike other checkpoint mutants, chk1 mutants were only mildly sensitive to DNA damage, indicating that checkpoint functions besides cell cycle arrest influence damage sensitivity. Another kinase, Rad53, was required to both maintain active cyclin-dependent kinase 1, Cdk1(Cdc28), and prevent anaphase entry after checkpoint activation. Evidence suggests that Rad53 exerts its role in checkpoint control through regulation of the Polo kinase Cdc5. These results support a model in which Chk1 and Rad53 function in parallel through Pds1 and Cdc5, respectively, to prevent anaphase entry and mitotic exit after DNA damage. This model provides a possible explanation for the role of Cdc5 in DNA damage checkpoint adaptation.