Error-prone repair of stalled replication forks drives mutagenesis and loss of heterozygosity in haploinsufficient BRCA1 cells

Mol Cell. 2022 Oct 20;82(20):3781-3793.e7. doi: 10.1016/j.molcel.2022.08.017. Epub 2022 Sep 12.


Germline mutations in the BRCA genes are associated with a higher risk of carcinogenesis, which is linked to an increased mutation rate and loss of the second unaffected BRCA allele (loss of heterozygosity, LOH). However, the mechanisms triggering mutagenesis are not clearly understood. The BRCA genes contain high numbers of repetitive DNA sequences. We detected replication forks stalling, DNA breaks, and deletions at these sites in haploinsufficient BRCA cells, thus identifying the BRCA genes as fragile sites. Next, we found that stalled forks are repaired by error-prone pathways, such as microhomology-mediated break-induced replication (MMBIR) in haploinsufficient BRCA1 breast epithelial cells. We detected MMBIR mutations in BRCA1 tumor cells and noticed deletions-insertions (>50 bp) at the BRCA1 genes in BRCA1 patients. Altogether, these results suggest that under stress, error-prone repair of stalled forks is upregulated and induces mutations, including complex genomic rearrangements at the BRCA genes (LOH), in haploinsufficient BRCA1 cells.

Keywords: BRCA; DNA repair; MMBIR; fork stalling; fragile sites; mutagenesis; replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • BRCA1 Protein* / genetics
  • BRCA1 Protein* / metabolism
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism
  • DNA Repair
  • DNA Replication*
  • Genes, BRCA1
  • Humans
  • Loss of Heterozygosity
  • Mutagenesis


  • BRCA1 Protein
  • BRCA2 Protein
  • BRCA1 protein, human