PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways.
PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways.
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DOI：
10.1093/nar/gku174
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发表时间：
2014-05
影响因子：
14.9
通讯作者：
Dantzer F
中科院分区：
文献类型：
--
作者：
Beck C;Boehler C;Guirouilh Barbat J;Bonnet ME;Illuzzi G;Ronde P;Gauthier LR;Magroun N;Rajendran A;Lopez BS;Scully R;Boussin FD;Schreiber V;Dantzer F
毒性双链断裂(DSB)的修复是维持基因组完整性的关键。处理DSB的主要机制有：同源重组(HR)和经典或替代的非同源末端连接(C-NHEJ与A-EJ)。由于这些途径都在竞争DSB的修复，因此选择合适的修复途径至关重要。在影响这一选择的机制中，脱氧核糖核酸(DNA)末端切除在推动细胞向HR方向发展方面发挥了关键作用，而准确的C-NHEJ受到抑制。此外，末端切除促进了容易出错的A-EJ。越来越多的证据表明，多聚(ADP-核糖)聚合酶3(PARP3，也称为ARTD3)在细胞对DSB的反应中发挥着重要作用。在这项工作中，我们揭示了PARP3的一个特殊功能，即与Ku80一起限制DNA末端切除，从而帮助在HR和NHEJ途径之间做出选择。PARP3与Ku70/Ku80相互作用并使其PARylate。PARP3的缺失损害了YFP-Ku80在激光诱导的DNA损伤部位的募集，并导致BRCA1和53BP1之间的失衡。这两个事件都会导致C-NHEJ的准确性受损，并伴随着DNA末端切除的增加。然而，当PARP3沉默时，HR显著降低，而增强的末端切除导致A-EJ期间的突变缺失。因此，PARP3的缺失使人对产生DSB的抗肿瘤药物过敏。
The repair of toxic double-strand breaks (DSB) is critical for the maintenance of genome integrity. The major mechanisms that cope with DSB are: homologous recombination (HR) and classical or alternative nonhomologous end joining (C-NHEJ versus A-EJ). Because these pathways compete for the repair of DSB, the choice of the appropriate repair pathway is pivotal. Among the mechanisms that influence this choice, deoxyribonucleic acid (DNA) end resection plays a critical role by driving cells to HR, while accurate C-NHEJ is suppressed. Furthermore, end resection promotes error-prone A-EJ. Increasing evidence define Poly(ADP-ribose) polymerase 3 (PARP3, also known as ARTD3) as an important player in cellular response to DSB. In this work, we reveal a specific feature of PARP3 that together with Ku80 limits DNA end resection and thereby helps in making the choice between HR and NHEJ pathways. PARP3 interacts with and PARylates Ku70/Ku80. The depletion of PARP3 impairs the recruitment of YFP-Ku80 to laser-induced DNA damage sites and induces an imbalance between BRCA1 and 53BP1. Both events result in compromised accurate C-NHEJ and a concomitant increase in DNA end resection. Nevertheless, HR is significantly reduced upon PARP3 silencing while the enhanced end resection causes mutagenic deletions during A-EJ. As a result, the absence of PARP3 confers hypersensitivity to anti-tumoral drugs generating DSB.
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影响因子：
64.8
作者：
Costelloe, Thomas;Louge, Raphael;Tomimatsu, Nozomi;Mukherjee, Bipasha;Martini, Emmanuelle;Khadaroo, Basheer;Dubois, Kenny;Wiegant, Wouter W.;Thierry, Agnes;Burma, Sandeep;van Attikum, Haico;Llorente, Bertrand
通讯作者：
Llorente, Bertrand
影响因子：
4
作者：
Chapman, J. Ross;Sossick, Alex J.;Jackson, Stephen P.
通讯作者：
Jackson, Stephen P.
由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调节回路控制 DNA 修复途径的选择。
影响因子：
16
作者：
Escribano-Diaz, Cristina;Orthwein, Alexandre;Durocher, Daniel
通讯作者：
Durocher, Daniel
影响因子：
4
作者：
Augustin, A;Spenlehauer, C;de Murcia, G
通讯作者：
de Murcia, G
影响因子：
5.3
作者：
Dronkert, MLG;Beverloo, HB;Kanaar, R
通讯作者：
Kanaar, R