Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry.
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.
Mesh Terms:
Amino Acid Substitution, BRCA2 Protein, Breast Neoplasms, Cell Line, Female, HeLa Cells, Homologous Recombination, Humans, Models, Biological, Molecular Mimicry, Mutagenesis, Site-Directed, Nuclear Magnetic Resonance, Biomolecular, Proteasome Endopeptidase Complex, Protein Subunits, Rad51 Recombinase, Recombinant Proteins, Replication Protein A
Amino Acid Substitution, BRCA2 Protein, Breast Neoplasms, Cell Line, Female, HeLa Cells, Homologous Recombination, Humans, Models, Biological, Molecular Mimicry, Mutagenesis, Site-Directed, Nuclear Magnetic Resonance, Biomolecular, Proteasome Endopeptidase Complex, Protein Subunits, Rad51 Recombinase, Recombinant Proteins, Replication Protein A
Mol. Cell
Date: Jul. 16, 2015
PubMed ID: 26145171
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