Molecular Cell
Volume 68, Issue 2, 19 October 2017, Pages 414-430.e8
Journal home page for Molecular Cell

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

https://doi.org/10.1016/j.molcel.2017.09.036Get rights and content
Under an Elsevier user license
open archive

Highlights

  • SNF2 fork remodelers promote nascent DNA degradation in BRCA1/2-deficient cells

  • Fork remodelers favor MRE11 binding to stalled forks in BRCA1-deficient cells

  • Forks regressed by fork remodelers are degraded by MRE11 in BRCA1-deficient cells

  • Depletion of fork remodelers reduces genomic instability in BRCA1/2-deficient cells

Summary

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

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

Cited by (0)

9

These authors contributed equally

10

These authors contributed equally

11

Lead Contact