And-1 coordinates with CtIP for efficient homologous recombination and DNA damage checkpoint maintenance.
And-1 coordinates with CtIP for efficient homologous recombination and DNA damage checkpoint maintenance.
复制标题
And-1 与 CtIP 配合，实现高效同源重组和 DNA 损伤检查点维护
DOI：
10.1093/nar/gkw1212
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发表时间：
2017-03-17
影响因子：
14.9
通讯作者：
Pei H
中科院分区：
文献类型：
--
作者：
Chen Y;Liu H;Zhang H;Sun C;Hu Z;Tian Q;Peng C;Jiang P;Hua H;Li X;Pei H
摘要为了防止基因组的不稳定性，细胞通过阻断细胞周期进程和启动DNA修复来应对DNA损伤。DNA断裂的同源重组修复需要CtIP依赖的DNA末端切除，这被认为在CHK 1激酶激活以诱导细胞周期检查点中起关键作用。但其机制仍不完全清楚。在这里，我们建立和-1，复制体组件，促进DNA末端切除和DNA修复的同源重组。在机制上，And-1与CtIP相互作用并调节CtIP向DNA损伤位点的募集。And-1定位于依赖于MDC 1-RNF 8途径的DNA损伤位点，并且是抵抗许多DNA损伤和复制应激诱导剂所必需的。此外，我们表明，和-1-CtIP轴是至关重要的持续ATR-CHK 1检查点信号和维持内S-和G2-阶段检查点。因此，我们的研究结果确定And-1作为一种新的DNA修复调节因子，并揭示了复制体如何调节DNA损伤诱导的检查点和基因组稳定性。
Abstract To prevent genomic instability, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homologous recombination repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of CHK1 kinase to induce the cell cycle checkpoint. But the mechanism is still not fully understood. Here, we establish that And-1, a replisome component, promotes DNA-end resection and DNA repair by homologous recombination. Mechanistically, And-1 interacts with CtIP and regulates CtIP recruitment to DNA damage sites. And-1 localizes to sites of DNA damage dependent on MDC1-RNF8 pathway, and is required for resistance to many DNA-damaging and replication stress-inducing agents. Furthermore, we show that And-1-CtIP axis is critically required for sustained ATR–CHK1 checkpoint signaling and for maintaining both the intra-S- and G2-phase checkpoints. Our findings thus identify And-1 as a novel DNA repair regulator and reveal how the replisome regulates the DNA damage induced checkpoint and genomic stability.