Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A
Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A
复制标题
DOI：
10.1016/s1535-6108(03)00048-5
复制
发表时间：
2003-03-01
期刊：
影响因子：
50.3
通讯作者：
Lukas, J
中科院分区：
文献类型：
--
作者：
Sorensen, CS;Syluåsen, RG;Lukas, J
Chk1激酶协调细胞周期进程并保持基因组完整性。在这里，我们表明，化学或基因消融人类Chk1触发超生理积累的S期促进Cdc25A磷酸酶，防止电离辐射（IR）诱导的Cdc25A降解，并引起抗辐射DNA合成（RDS）。Cdc25A在未受干扰的S期的基础营业额需要Chk1依赖的丝氨酸123，178，278和292的磷酸化。IR诱导的Cdc25A蛋白水解的加速与增加磷酸盐掺入这些残基产生的Chk1和Chk2激酶的联合作用。最后，需要通过ATM磷酸化Chk1以完全加速IR诱导的Cdc25A降解。我们的研究结果提供的证据表明，哺乳动物的S期检查点功能，通过放大生理操作，Chk1依赖的机制。
Chk1 kinase coordinates cell cycle progression and preserves genome integrity. Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase-promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A, and caused radioresistant DNA synthesis (RDS). The basal turnover of Cdc25A operating in unperturbed S phase required Chk1-dependent phosphorylation of serines 123, 178, 278, and 292. IR-induced acceleration of Cdc25A proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of Chk1 and Chk2 kinases. Finally, phosphorylation of Chk1 by ATM was required to fully accelerate the IR-induced degradation of Cdc25A. Our results provide evidence that the mammalian S phase checkpoint functions via amplification of physiologically operating, Chk1-dependent mechanisms.