BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation
BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation
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DOI：
10.1016/j.celrep.2016.12.042
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发表时间：
2017-01-10
期刊：
影响因子：
8.8
通讯作者：
Shibata, Atsushi
中科院分区：
文献类型：
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作者：
Isono, Mayu;Niimi, Atsuko;Shibata, Atsushi
BRCA1通过激活dna末端切除促进同源重组（homologous recombination， HR）。相反，53BP1形成抑制dna末端切除的屏障。在这里，我们发现BRCA1通过解除53bp1依赖的屏障来促进dna末端切除。我们发现53BP1在S/G(2)期被ATM磷酸化，促进RIF1的募集，从而抑制肿瘤切除。尽管存在未修复的DNA双链断裂（DSBs）， 53BP1会迅速去磷酸化，RIF1释放。当切除因CtIP/MRE11内切酶抑制而受损时，53BP1磷酸化和RIF1由于持续的ATM信号而持续。BRCA1缺失也维持53BP1磷酸化和RIF1募集。我们发现磷酸酶PP4C在53BP1去磷酸化和RIF1释放中起主要作用。BRCA1或PP4C缺失会损害53BP1的重新定位、EXO1的招募和HR进展。53BP1或RIF1缺失可恢复pp4c缺失细胞的切除、RAD51加载和HR。我们的研究结果表明，BRCA1促进pp4c依赖性53BP1去磷酸化和RIF1释放，指导HR修复。
BRCA1 promoteshomologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G(2) phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling. BRCA1 depletion also sustains 53BP1 phosphorylation and RIF1 recruitment. We identify the phosphatase PP4C as having a major role in 53BP1 dephosphorylation and RIF1 release. BRCA1 or PP4C depletion impairs 53BP1 repositioning, EXO1 recruitment, and HR progression. 53BP1 or RIF1 depletion restores resection, RAD51 loading, and HR in PP4C-depleted cells. Our findings suggest that BRCA1 promotes PP4C-dependent 53BP1 dephosphorylation and RIF1 release, directing repair toward HR.