The role of Dbf4/Drf1-dependent kinase Cdc7 in DNA-damage checkpoint control.
The role of Dbf4/Drf1-dependent kinase Cdc7 in DNA-damage checkpoint control.
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DOI：
10.1016/j.molcel.2008.12.005
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发表时间：
2008-12-26
期刊：
影响因子：
16
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Tsuji T;Lau E;Chiang GG;Jiang W
Dbf4/ drf1依赖的s期促进激酶Cdc7 （Ddk）被认为是抑制DNA复制的s期检查点机制灭活的重要靶点。然而，我们在这里表明，在爪蟾卵提取物和哺乳动物细胞中，DNA损伤诱导的s期检查点反应中，复合物的形成、染色质结合和Ddk的激酶活性并未受到抑制。相反，我们发现Ddk在调节s期检查点信号传导中起积极作用。在爪蟾卵提取物中添加纯化的Ddk或在HeLa细胞中过表达Dbf4可下调ATR-Chk1检查点信号，并覆盖DNA损伤剂诱导的DNA复制和细胞周期进程的抑制。这些结果表明，Ddk作为上游调节因子监测s期检查点信号传导。我们提出Ddk通过衰减检查点信号并在s期检查点恢复期间触发DNA复制重新启动来调节s期检查点控制。
The Dbf4/Drf1-dependent S-phase promoting kinase Cdc7 (Ddk) is thought to be an essential target inactivated by the S-phase checkpoint machinery that inhibits DNA replication. However, we show here that the complex formation, chromatin-association, and kinase activity of Ddk are not inhibited during the DNA damage-induced S-phase checkpoint response in Xenopus egg extracts and mammalian cells. Instead, we find that Ddk plays an active role in regulating S-phase checkpoint signaling. Addition of purified Ddk to Xenopus egg extracts or overexpression of Dbf4 in HeLa cells downregulates ATR-Chk1 checkpoint signaling and overrides the inhibition of DNA replication and cell cycle progression induced by DNA damaging agents. These results indicate that Ddk functions as an upstream regulator to monitor S-phase checkpoint signaling. We propose that Ddk modulates the S-phase checkpoint control by attenuating checkpoint signaling and triggering DNA replication re-initiation during the S-phase checkpoint recovery.