FIGNL1 inhibits homologous recombination in BRCA2 deficient cells by dissociating RAD51 filaments

Science. 2025 Oct 30;390(6772):eadt1210. doi: 10.1126/science.adt1210. Epub 2025 Oct 30.

Abstract

Homologous recombination (HR) deficiency upon Breast Cancer Gene 2 (BRCA2) loss arises from defects in the formation of RAD51 nucleoprotein filaments. We demonstrate that loss of the anti-recombinase Fidgetin Like 1 (FIGNL1) retains RAD51 loading at DNA double-stranded breaks (DSBs) in BRCA2-deficient cells, leading to genome stability, HR proficiency, and viability of BRCA2-deficient mouse embryonic stem cells. Mechanistically, we demonstrate that strand invasion and subsequent HR defects upon BRCA2 loss primarily arise from the unrestricted removal of RAD51 from DSB sites by FIGNL1, rather than from defective RAD51 loading. Furthermore, we identify that the MMS22L-TONSL complex interacts with FIGNL1 and is critical for HR in BRCA2/FIGNL1 double-deficient cells. These findings identify a pathway for tightly regulating RAD51 activity to promote efficient HR, offering insights into mechanisms of chemoresistance in BRCA2-deficient tumors.

MeSH terms

  • Animals
  • BRCA2 Protein* / deficiency
  • BRCA2 Protein* / genetics
  • DNA Breaks, Double-Stranded
  • DNA-Binding Proteins / metabolism
  • Genomic Instability
  • Homologous Recombination*
  • Humans
  • Mice
  • Mouse Embryonic Stem Cells
  • Rad51 Recombinase* / metabolism
  • Recombinational DNA Repair

Substances

  • Rad51 Recombinase
  • BRCA2 Protein
  • BRCA2 protein, mouse
  • Rad51 protein, mouse
  • DNA-Binding Proteins