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CtIP-mediated fork protection synergizes with BRCA1 to suppress genomic instability upon DNA replication stress


Przetocka, Sara; Porro, Antonio; Bolck, Hella A; Walker, Christina; Lezaja, Aleksandra; Trenner, Anika; von Aesch, Christine; Himmels, Sarah-Felicitas; D’Andrea, Alan D; Ceccaldi, Raphael; Altmeyer, Matthias; Sartori, Alessandro A (2018). CtIP-mediated fork protection synergizes with BRCA1 to suppress genomic instability upon DNA replication stress. Molecular Cell, 72(3):568-582.e6.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research

05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:Cell Biology, Molecular Biology, BRCA1; BRCA2; CtIP; DNA replication stress; DNA2; MRE11; fork protection; genome stability; homologous recombination; synthetic lethaility
Language:English
Date:1 November 2018
Deposited On:21 Nov 2018 15:11
Last Modified:14 Jan 2019 15:46
Publisher:Cell Press (Elsevier)
ISSN:1097-2765
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.molcel.2018.09.014
PubMed ID:30344097
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_156023
  • : Project TitleMechanisitic insights into the regulation of DNA double-strand break repair
  • : FunderSNSF
  • : Grant ID31003A_176161
  • : Project TitleKeeping DNA repair nucleases in check to maintain genome stability

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