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

Zhao W, Vaithiyalingam S, San Filippo J, Maranon DG, Jimenez-Sainz J, Fontenay GV, Kwon Y, Leung SG, Lu L, Jensen RB, Chazin WJ, Wiese C, Sung P
Mol Cell. 2015 59 (2): 176-87

PMID: 26145171 · PMCID: PMC4506714 · DOI:10.1016/j.molcel.2015.05.032

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (17)

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

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