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

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


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.

Keywords: BRCA1; BRCA2; CtIP; DNA replication stress; DNA2; MRE11; fork protection; genome stability; homologous recombination; synthetic lethaility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein
  • BRCA2 Protein
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology*
  • Cell Line
  • DNA Breaks, Double-Stranded
  • DNA Helicases / physiology
  • DNA Repair
  • DNA Replication / physiology*
  • DNA-Binding Proteins
  • Deoxyribonucleases
  • Endodeoxyribonucleases
  • Genomic Instability / physiology
  • Homologous Recombination / genetics
  • Humans
  • MRE11 Homologue Protein / metabolism
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology*
  • Protein Binding


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • Carrier Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • Nuclear Proteins
  • Deoxyribonucleases
  • Endodeoxyribonucleases
  • MRE11 Homologue Protein
  • RBBP8 protein, human
  • DNA Helicases
  • DNA2 protein, human