Conservation of the Chk1 checkpoint pathway in mammals: Linkage of DNA damage to Cdk regulation through Cdc25
Conservation of the Chk1 checkpoint pathway in mammals: Linkage of DNA damage to Cdk regulation through Cdc25
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DOI：
10.1126/science.277.5331.1497
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发表时间：
1997-09-05
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;Wong, C;Elledge, SJ
在DNA损伤的反应中，哺乳动物细胞通过控制关键的细胞周期调节因子来阻止细胞周期的进展。一个人类基因被鉴定编码蛋白质Chk1，一个同源的分裂糖酵母pombe Chk1蛋白激酶，这是DNA损伤检查点所必需的。人类Chk1蛋白被修饰以响应DNA损伤。在体外，Chk1结合并磷酸化双特异性蛋白磷酸酶Cdc25A、Cdc25B和Cdc25C，这些蛋白磷酸酶通过去磷酸化周期蛋白依赖性激酶来控制细胞周期转变。Chk1磷酸化丝氨酸-216上的Cdc25C。正如本期Peng等人的论文所示，丝氨酸-216的磷酸化产生了14-3-3蛋白的结合位点，抑制了磷酸酶的功能。这些结果表明，在DNA损伤的响应模型中，Chk1磷酸化并抑制Cdc25C，从而阻止Cdc2-cyclin B复合物的激活和有丝分裂进入。
In response to DNA damage, mammalian cells prevent cell cycle progression through the control of critical cell cycle regulators. A human gene was identified that encodes the protein Chk1, a homolog of the Schizosaccharomyces pombe Chk1 protein kinase, which is required for the DNA damage checkpoint. Human Chk1 protein was modified in response to DNA damage. In vitro Chk1 bound to and phosphorylated the dual-specificity protein phosphatases Cdc25A, Cdc25B, and Cdc25C, which control cell cycle transitions by dephosphorylating cyclin-dependent kinases. Chk1 phosphorylates Cdc25C on serine-216. As shown in an accompanying paper by Peng et al. in this issue, serine-216 phosphorylation creates a binding site for 14-3-3 protein and inhibits function of the phosphatase. These results suggest a model whereby in response to DNA damage, Chk1 phosphorylates and inhibits Cdc25C, thus preventing activation of the Cdc2-cyclin B complex and mitotic entry.