Poly(ADP-ribose) polymerase-1 antagonizes DNA resection at double-strand breaks
Poly(ADP-ribose) polymerase-1 antagonizes DNA resection at double-strand breaks
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DOI：
10.1038/s41467-019-10741-9
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发表时间：
2019-07-04
影响因子：
16.6
通讯作者：
Masson, Jean-Yves
中科院分区：
文献类型：
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作者：
Caron, Marie-Christine;Sharma, Ajit K.;Masson, Jean-Yves
PARP-1通过DNA双链断裂（DSB）快速募集和激活。在活化后，PARP-1合成由ADP-核糖单元组成的结构复杂的聚合物，其促进局部染色质松弛和DNA修复因子的募集。在这里，我们确定了PARP-1在DNA DSB切除中的功能。值得注意的是，PARP-1的抑制导致过度切除的DNA DSB。我们发现PARP-1的缺失和过度切除与断裂部位Ku、53 BP 1和RIF 1切除抑制剂的缺失相关。DNA幕帘分析表明，EXO 1介导的切除被PARP-1阻断。此外，PARP-1废除导致增加的DNA切除轨迹和细胞中同源重组的增加。因此，我们的研究结果将PARP-1激活作为DNA DSB修复激活和切除调控的关键早期事件。因此，我们的工作对PARP抑制的临床应用和有效性具有直接影响，PARP抑制用于治疗各种恶性肿瘤。
PARP-1 is rapidly recruited and activated by DNA double-strand breaks (DSBs). Upon activation, PARP-1 synthesizes a structurally complex polymer composed of ADP-ribose units that facilitates local chromatin relaxation and the recruitment of DNA repair factors. Here, we identify a function for PARP-1 in DNA DSB resection. Remarkably, inhibition of PARP-1 leads to hyperresected DNA DSBs. We show that loss of PARP-1 and hyperresection are associated with loss of Ku, 53BP1 and RIF1 resection inhibitors from the break site. DNA curtains analysis show that EXO1-mediated resection is blocked by PARP-1. Furthermore, PARP-1 abrogation leads to increased DNA resection tracks and an increase of homologous recombination in cellulo. Our results, therefore, place PARP-1 activation as a critical early event for DNA DSB repair activation and regulation of resection. Hence, our work has direct implications for the clinical use and effectiveness of PARP inhibition, which is prescribed for the treatment of various malignancies.