Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks.
Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks.
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DOI：
10.1093/nar/gkp1164
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发表时间：
2010-04
影响因子：
14.9
通讯作者：
Khanna KK
中科院分区：
文献类型：
--
作者：
Bolderson E;Tomimatsu N;Richard DJ;Boucher D;Kumar R;Pandita TK;Burma S;Khanna KK
DNA双链断裂（DSB）修复是一个多阶段的过程，通过同源重组途径修复DSB而不丢失遗传信息或保真度。这个过程中的一个重要步骤是在断裂位点产生延伸的单链DNA（ssDNA）区域。该ssDNA用于诱导细胞周期检查点，并且是Rad51介导的姐妹染色单体链侵入所需的。在这里，我们表明，人类核酸外切酶1（Exo1）是所需的正常修复DSB的HR。细胞耗尽Exo1显示染色体不稳定性和超敏性电离辐射（IR）曝光。我们发现Exo1在DSB中迅速积累，并且是RPA和Rad51募集到DSB位点所必需的，这表明Exo1在ssDNA生成中的作用。有趣的是，ATM对Exo1的磷酸化似乎可以调节切除后Exo1的活性，从而实现最佳的Rad51加载和HR修复的完成。这些数据确立了Exo1在人类细胞中DSB切除中的作用，突出了Exo1通过HR进行DSB修复的关键要求，从而维持基因组稳定性。
DNA double-strand break (DSB) repair via the homologous recombination pathway is a multi-stage process, which results in repair of the DSB without loss of genetic information or fidelity. One essential step in this process is the generation of extended single-stranded DNA (ssDNA) regions at the break site. This ssDNA serves to induce cell cycle checkpoints and is required for Rad51 mediated strand invasion of the sister chromatid. Here, we show that human Exonuclease 1 (Exo1) is required for the normal repair of DSBs by HR. Cells depleted of Exo1 show chromosomal instability and hypersensitivity to ionising radiation (IR) exposure. We find that Exo1 accumulates rapidly at DSBs and is required for the recruitment of RPA and Rad51 to sites of DSBs, suggesting a role for Exo1 in ssDNA generation. Interestingly, the phosphorylation of Exo1 by ATM appears to regulate the activity of Exo1 following resection, allowing optimal Rad51 loading and the completion of HR repair. These data establish a role for Exo1 in resection of DSBs in human cells, highlighting the critical requirement of Exo1 for DSB repair via HR and thus the maintenance of genomic stability.
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影响因子：
64.5
作者：
Buis J;Wu Y;Deng Y;Leddon J;Westfield G;Eckersdorff M;Sekiguchi JM;Chang S;Ferguson DO
通讯作者：
Ferguson DO
影响因子：
16
作者：
Shiotani, Bunsyo;Zou, Lee
通讯作者：
Zou, Lee
影响因子：
3.8
作者：
Di Virgilio, Michela;Ying, Carol Y.;Gautier, Jean
通讯作者：
Gautier, Jean
DOI：
10.1073/pnas.0809380105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Nimonkar, Almitabh V.;Ozsoy, A. Zeynep;Kowalczykowski, Stephen C.
通讯作者：
Kowalczykowski, Stephen C.
影响因子：
11.4
作者：
Morin, Isabelle;Ngo, Hien-Ping;Greenall, Amanda;Zubko, Mikhajlo K.;Morrice, Nick;Lydall, David
通讯作者：
Lydall, David