BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing

Nature. 2017 Oct 19;550(7676):360-365. doi: 10.1038/nature24060. Epub 2017 Oct 4.

Abstract

The tumour suppressor complex BRCA1-BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination. During this process, BRCA1-BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumour suppressor complex, BRCA2-PALB2, and the recombinase RAD51. Here, by examining purified wild-type and mutant BRCA1-BARD1, we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. We provide evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions show compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. Our results identify a late role of BRCA1-BARD1 in homologous recombination, an attribute of the tumour suppressor complex that could be targeted in cancer therapy.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism
  • Base Pairing*
  • Chromosome Pairing*
  • Fanconi Anemia Complementation Group N Protein / genetics
  • Fanconi Anemia Complementation Group N Protein / metabolism
  • Genes, BRCA1
  • Genes, BRCA2
  • Humans
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation
  • Protein Binding
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism*
  • Recombinational DNA Repair* / genetics
  • Sequence Homology, Nucleic Acid*
  • Templates, Genetic
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Fanconi Anemia Complementation Group N Protein
  • Multiprotein Complexes
  • PALB2 protein, human
  • Tumor Suppressor Proteins
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases
  • RAD51 protein, human
  • Rad51 Recombinase