CtIP 介导的叉保护与 BRCA1 协同作用，在 DNA 复制应激下抑制基因组不稳定性。

CtIP-Mediated Fork Protection Synergizes with BRCA1 to Suppress Genomic Instability upon DNA Replication Stress.

机构信息

Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

出版信息

Mol Cell. 2018 Nov 1;72(3):568-582.e6. doi: 10.1016/j.molcel.2018.09.014. Epub 2018 Oct 18.

DOI:10.1016/j.molcel.2018.09.014

PMID:30344097

Abstract

Protecting stalled DNA replication forks from degradation by promiscuous nucleases is essential to prevent genomic instability, a major driving force of tumorigenesis. Several proteins commonly associated with the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) have been implicated in the stabilization of stalled forks. Human CtIP, in conjunction with the MRE11 nuclease complex, plays an important role in HR by promoting DSB resection. Here, we report an unanticipated function for CtIP in protecting reversed forks from degradation. Unlike BRCA proteins, which defend nascent DNA strands from nucleolytic attack by MRE11, we find that CtIP protects perturbed forks from erroneous over-resection by DNA2. Finally, we uncover functionally synergistic effects between CtIP and BRCA1 in mitigating replication-stress-induced genomic instability. Collectively, our findings reveal a DSB-resection- and MRE11-independent role for CtIP in preserving fork integrity that contributes to the survival of BRCA1-deficient cells.

摘要

保护停滞的 DNA 复制叉免受核酸内切酶的降解对于防止基因组不稳定性至关重要，基因组不稳定性是肿瘤发生的主要驱动力。几种通常与同源重组 (HR) 修复 DNA 双链断裂 (DSB) 相关的蛋白质被牵连到稳定停滞的复制叉中。人类 CtIP 与 MRE11 核酸酶复合物一起，通过促进 DSB 切除在 HR 中发挥重要作用。在这里，我们报告了 CtIP 在保护反转叉免受降解方面的一个意外功能。与 BRCA 蛋白不同，BRCA 蛋白可以保护新生 DNA 链免受 MRE11 的核酸内切攻击，我们发现 CtIP 可以保护受损的叉子免受 DNA2 的错误过度切除。最后，我们发现 CtIP 和 BRCA1 之间在减轻复制应激引起的基因组不稳定性方面具有功能协同效应。总的来说，我们的发现揭示了 CtIP 在保护分叉完整性方面的 DSB 切除和 MRE11 非依赖性作用，有助于 BRCA1 缺陷细胞的存活。