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

被引:93
|
作者
Przetocka, Sara [1 ]
Porro, Antonio [1 ]
Bolck, Hella A. [1 ]
Walker, Christina [1 ]
Lezaja, Aleksandra [2 ]
Trenner, Anika [1 ]
von Aesch, Christine [1 ]
Himmels, Sarah-Felicitas [1 ]
D'Andrea, Alan D. [3 ]
Ceccaldi, Raphael [3 ]
Altmeyer, Matthias [2 ]
Sartori, Alessandro A. [1 ]
机构
[1] Univ Zurich, Inst Mol Canc Res, Winterthurerstr 190, CH-8057 Zurich, Switzerland
[2] Univ Zurich, Dept Mol Mech Dis, Winterthurerstr 190, CH-8057 Zurich, Switzerland
[3] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA
基金
瑞士国家科学基金会; 欧洲研究理事会;
关键词
DOUBLE-STRAND BREAK; END RESECTION; HUMAN-CELLS; DAMAGE CHECKPOINT; DEFICIENT CELLS; REPAIR; STABILITY; ENDONUCLEASE; COLLAPSE; REVERSAL;
D O I
10.1016/j.molcel.2018.09.014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:568 / +
页数:21
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