Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers

Mol Cell. 2017 Oct 19;68(2):414-430.e8. doi: 10.1016/j.molcel.2017.09.036.


To ensure the completion of DNA replication and maintenance of genome integrity, DNA repair factors protect stalled replication forks upon replication stress. Previous studies have identified a critical role for the tumor suppressors BRCA1 and BRCA2 in preventing the degradation of nascent DNA by the MRE11 nuclease after replication stress. Here we show that depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells. In addition to SMARCAL1, other SNF2-family fork remodelers, including ZRANB3 and HLTF, cause nascent DNA degradation and genomic instability in BRCA1/2-deficient cells upon replication stress. Our observations indicate that nascent DNA degradation in BRCA1/2-deficient cells occurs as a consequence of MRE11-dependent nucleolytic processing of reversed forks generated by fork remodelers. These studies provide mechanistic insights into the processes that cause genome instability in BRCA1/2-deficient cells.

Keywords: BRCA1 and BRCA2; DNA replication stress; HLTF; MRE11; RAD51; SMARCAL1; ZRANB3; breast and ovarian cancer; replication fork instability; replication fork reversal.

MeSH terms

  • BRCA2 Protein / deficiency*
  • Cell Line, Tumor
  • DNA Breaks*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Genomic Instability
  • Humans
  • MRE11 Homologue Protein
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / deficiency*


  • BRCA2 Protein
  • BRCA2 protein, human
  • DNA-Binding Proteins
  • HLTF protein, human
  • MRE11 protein, human
  • Transcription Factors
  • BRAP protein, human
  • Ubiquitin-Protein Ligases
  • SMARCAL1 protein, human
  • MRE11 Homologue Protein
  • DNA Helicases
  • ZRANB3 protein, human