EXD2 promotes homologous recombination by facilitating DNA end resection.
EXD2 promotes homologous recombination by facilitating DNA end resection.
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DOI：
10.1038/ncb3303
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发表时间：
2016-03
影响因子：
21.3
通讯作者：
Niedzwiedz W
中科院分区：
文献类型：
--
作者：
Broderick R;Nieminuszczy J;Baddock HT;Deshpande R;Gileadi O;Paull TT;McHugh PJ;Niedzwiedz W
通过同源重组（HR）修复DNA双链断裂（DSB）对于个体细胞和生物体的存活和基因组稳定性至关重要，而且还有助于物种的遗传多样性。HR中的关键步骤是MRN/CtIP依赖性末端切除，其产生随后的链交换反应所需的3′单链DNA突出端。在这里，我们确定EXD 2（EXDL 2）作为DSB切除和有效HR所必需的核酸外切酶。EXD 2以损伤依赖性方式被招募到染色质中，并赋予对DSB诱导剂的抗性。EXD 2与MRN复合物在功能上相互作用，通过其3′-5′核酸外切酶活性加速切除，有效处理含有切口的dsDNA底物。最后，我们确定EXD 2刺激短距离和长距离DSB切除，因此与MRE 11一起是有效HR所必需的。这确立了EXD 2在控制染色体断裂修复的初始步骤中的关键作用。
Repair of DNA double strand breaks (DSBs) by homologous recombination (HR) is critical for survival and genome stability of individual cells and organisms, but also contributes to the genetic diversity of species. A critical step in HR is MRN/CtIP-dependent end-resection that generates the 3′ single-stranded DNA overhangs required for the subsequent strand exchange reaction. Here, we identify EXD2 (EXDL2) as an exonuclease essential for DSB resection and efficient HR. EXD2 is recruited to chromatin in a damage-dependent manner and confers resistance to DSB-inducing agents. EXD2 functionally interacts with the MRN-complex to accelerate resection via its 3′-5′ exonuclease activity that efficiently processes dsDNA substrates containing nicks. Finally, we establish that EXD2 stimulates both short and long-range DSB resection, and thus together with MRE11 is required for efficient HR. This establishes a key role for EXD2 in controlling the initial steps of chromosomal break repair.