一个由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调控回路控制 DNA 修复途径的选择。

A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice.

机构信息

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.

出版信息

Mol Cell. 2013 Mar 7;49(5):872-83. doi: 10.1016/j.molcel.2013.01.001. Epub 2013 Jan 17.

DOI:10.1016/j.molcel.2013.01.001

Abstract

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.

摘要

DNA 双链断裂 (DSB) 修复途径的选择受 53BP1 和 BRCA1 相反活性的控制。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)。在这里，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。ATM 依赖性磷酸化的 53BP1 将 RIF1 物理募集到 DSB 位点，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 和其相互作用蛋白 CtIP 强烈拮抗 RIF1 在 DSB 位点的积累。最后，我们表明，RIF1 的耗竭能够恢复 BRCA1 耗尽细胞中的末端切除和 RAD51 加载。因此，这项工作鉴定了一个由 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，以确保在 G1 期 NHEJ 占主导地位，而从 S 期开始 HR 更有利。