A Cell Cycle-Dependent Regulatory Circuit Composed of 53BP1-RIF1 and BRCA1-CtIP Controls DNA Repair Pathway Choice
A Cell Cycle-Dependent Regulatory Circuit Composed of 53BP1-RIF1 and BRCA1-CtIP Controls DNA Repair Pathway Choice
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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。
DOI：
10.1016/j.molcel.2013.01.001
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发表时间：
2013-03-07
期刊：
影响因子：
16
通讯作者：
Durocher, Daniel
中科院分区：
文献类型：
--
作者：
Escribano-Diaz, Cristina;Orthwein, Alexandre;Durocher, Daniel
DNA双链断裂（DSB）修复途径的选择受53BP1和BRCA1相反活性的调控。53BP1刺激非同源末端连接（NHEJ），而BRCA1促进末端切除和同源重组（HR）。在此我们表明，53BP1是BRCA1在DSB位点积累的抑制剂，特别是在细胞周期的G1期。53BP1的ATM依赖性磷酸化在物理上招募RIF1到DSB位点，并且我们确定RIF1是DSB修复过程中53BP1的关键效应因子。值得注意的是，BRCA1及其相互作用伙伴CtIP强烈拮抗RIF1在DSB位点的积累。最后，我们表明RIF1的缺失能够在BRCA1缺失的细胞中恢复末端切除和RAD51的装载。因此，这项工作确定了一个由RIF1和BRCA1支撑的细胞周期调控回路，该回路控制DSB修复途径的选择，以确保NHEJ在G1期占主导，并且从S期开始HR更受青睐。
DNA double-strand break (DSB) repair pathway choice is governed by the opposing activities of 53BP1 and BRCA1. 53BP1 stimulates nonhomologous end joining (NHEJ), whereas BRCA1 promotes end resection and homologous recombination (HR). Here we show that 53BP1 is an inhibitor of BRCA1 accumulation at DSB sites, specifically in the G1 phase of the cell cycle. ATM-dependent phosphorylation of 53BP1 physically recruits RIF1 to DSB sites, and we identify RIF1 as the critical effector of 53BP1 during DSB repair. Remarkably, RIF1 accumulation at DSB sites is strongly antagonized by BRCA1 and its interacting partner CtIP. Lastly, we show that depletion of RIF1 is able to restore end resection and RAD51 loading in BRCA1-depleted cells. This work therefore identifies a cell cycle-regulated circuit, underpinned by RIF1 and BRCA1, that governs DSB repair pathway choice to ensure that NHEJ dominates in G1 and HR is favored from S phase onward.