A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2

Cancer Cell. 2012 Jul 10;22(1):106-16. doi: 10.1016/j.ccr.2012.05.015.

Abstract

Genes mutated in patients with Fanconi anemia (FA) interact with the DNA repair genes BRCA1 and BRCA2/FANCD1 to suppress tumorigenesis, but the molecular functions ascribed to them cannot fully explain all of their cellular roles. Here, we show a repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation. Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabilized RAD51 filaments. Moreover, FANCD2-mediated fork protection is epistatic with RAD51 functions, revealing an unanticipated fork protection pathway that connects FA genes to RAD51 and the BRCA1/2 breast cancer suppressors. Collective results imply a unified molecular mechanism for repair-independent functions of FA, RAD51, and BRCA1/2 proteins in preventing genomic instability and suppressing tumorigenesis.

Publication types

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

MeSH terms

  • BRCA2 Protein / genetics*
  • Cell Line, Transformed
  • DNA Replication*
  • Fanconi Anemia / genetics*
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Genomic Instability
  • Humans
  • Rad51 Recombinase / metabolism*

Substances

  • BRCA2 Protein
  • BRCA2 protein, human
  • RAD51 protein, human
  • Rad51 Recombinase