Institute of Molecular Cancer Research, University of Zurich, Switzerland.
EMBO Rep. 2010 Dec;11(12):962-8. doi: 10.1038/embor.2010.157. Epub 2010 Nov 5.
End resection of DNA-which is essential for the repair of DNA double-strand breaks (DSBs) by homologous recombination-relies first on the partnership between MRE11-RAD50-NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1). In this study, we show that the localization of EXO1 to DSBs depends on both CtIP and MRN. We also establish that CtIP interacts with EXO1 and restrains its exonucleolytic activity in vitro. Finally, we show that on exposure to camptothecin, depletion of EXO1 in CtIP-deficient cells increases the frequency of DNA-PK-dependent radial chromosome formation. Thus, our study identifies new functions of CtIP and EXO1 in DNA end resection and provides new information on the regulation of DSB repair pathways, which is a key factor in the maintenance of genome integrity.
DNA 的末端切除——这对同源重组修复 DNA 双链断裂（DSBs）至关重要——首先依赖于 MRE11-RAD50-NBS1（MRN）和 CtIP 之间的伙伴关系，然后是一个涉及解旋酶和核酸外切酶（如核酸外切酶 1（EXO1）的连续步骤。在这项研究中，我们表明 EXO1 到 DSBs 的定位依赖于 CtIP 和 MRN。我们还确定 CtIP 与 EXO1 相互作用，并在体外抑制其核酸外切酶活性。最后，我们表明，在用喜树碱处理后，CtIP 缺陷细胞中 EXO1 的耗竭会增加 DNA-PK 依赖性放射状染色体形成的频率。因此，我们的研究确定了 CtIP 和 EXO1 在 DNA 末端切除中的新功能，并提供了有关 DSB 修复途径调控的新信息，这是维持基因组完整性的关键因素。
