Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry

Mol Cell. 2015 Jul 16;59(2):176-87. doi: 10.1016/j.molcel.2015.05.032. Epub 2015 Jul 2.

Abstract

The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and in vivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically and functionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.

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

  • Amino Acid Substitution
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / therapy
  • Cell Line
  • Female
  • HeLa Cells
  • Homologous Recombination*
  • Humans
  • Models, Biological
  • Molecular Mimicry
  • Mutagenesis, Site-Directed
  • Nuclear Magnetic Resonance, Biomolecular
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Subunits
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Replication Protein A / chemistry
  • Replication Protein A / genetics
  • Replication Protein A / metabolism*

Substances

  • BRCA2 Protein
  • BRCA2 protein, human
  • Protein Subunits
  • RPA1 protein, human
  • Recombinant Proteins
  • Replication Protein A
  • SEM1 protein, human
  • RAD51 protein, human
  • Rad51 Recombinase
  • Proteasome Endopeptidase Complex