Sørensen Claus Storgaard, Syljuåsen Randi G, Falck Jacob, Schroeder Tine, Rönnstrand Lars, Khanna Kum Kum, Zhou Bin-Bing, Bartek Jiri, Lukas Jiri
Danish Cancer Society, Institute of Cancer Biology, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark.
Cancer Cell. 2003 Mar;3(3):247-58. doi: 10.1016/s1535-6108(03)00048-5.
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.
Chk1激酶协调细胞周期进程并维持基因组完整性。在此，我们表明，对人类Chk1进行化学或基因敲除会引发促进S期的Cdc25A磷酸酶超生理水平的积累，阻止电离辐射（IR）诱导的Cdc25A降解，并导致抗辐射DNA合成（RDS）。在未受干扰的S期发挥作用的Cdc25A的基础周转需要Chk1依赖的丝氨酸123、178、278和292的磷酸化。IR诱导的Cdc25A蛋白水解加速与Chk1和Chk2激酶共同作用使这些残基中磷酸掺入增加相关。最后，ATM对Chk1的磷酸化是充分加速IR诱导的Cdc25A降解所必需的。我们的结果提供了证据，表明哺乳动物S期检查点通过放大生理上起作用的、Chk1依赖的机制发挥功能。
