Cdc18 enforces long-term maintenance of the S phase checkpoint by anchoring the Rad3-Rad26 complex to chromatin
Cdc18 enforces long-term maintenance of the S phase checkpoint by anchoring the Rad3-Rad26 complex to chromatin
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DOI：
10.1016/j.molcel.2007.04.014
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发表时间：
2007-05-25
期刊：
影响因子：
16
通讯作者：
Nurse, Paul
中科院分区：
文献类型：
--
作者：
Hermand, Damien;Nurse, Paul
DNA复制是通过将Cdc 18募集到起点来启动的。在S期，Cdc 18发生依赖于CDK的破坏。我们表明，当DNA复制停止时，Cdc 18会持续存在于染色质结合的复合物中，包括检查点激酶Rad 3和Rad 26。Rad 26直接结合Cdc 18，并且是Rad 3募集到染色质所必需的。当DNA复制停滞时Cdc 18的耗尽导致Rad 3和Rad 26从染色质释放并进入异常有丝分裂，即使复制中间体仍然可以检测到。这些发现表明Cdc 18通过将Rad 3-Rad 26复合物锚定到染色质在检查点维持中起关键作用。Cdc 18在DNA复制停滞期间的持续性需要抑制S期CDK的S期检查点。我们建议S期阻滞激活S期检查点，阻断有丝分裂的开始并抑制Cdc 18降解，而稳定的Cdc 18反过来将Rad 3锚定在染色质上，以确保长期的检查点维持。
DNA replication is initiated by recruitment of Cdc18 to origins. During S phase, CDK-dependent destruction of Cdc18 occurs. We show that when DNA replication stalls, Cdc18 persists in a chromatin-bound complex including the checkpoint kinases Rad3 and Rad26. Rad26 directly binds Cdc18 and is required for Rad3 recruitment to chromatin. Depletion of Cdc18 when DNA replication is stalled leads to release of Rad3 and Rad26 from chromatin and entry into an aberrant mitosis even though replication intermediates can still be detected. These findings indicate that Cdc18 plays a pivotal role in checkpoint maintenance by anchoring the Rad3-Rad26 complex to chromatin. Cdc18 persistence during DNA-replication arrest requires the S phase checkpoint that inhibits the S phase CDK. We propose that S phase arrest activates the S phase checkpoint blocking mitosis onset and inhibiting Cdc18 degradation, and that the stabilized Cdc18, in turn, anchors Rad3 to chromatin to ensure long-term checkpoint maintenance.