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

Authors: Zhao, Weixing; Vaithiyalingam, Sivaraja; San Filippo, Joseph; Maranon, David G; Jimenez-Sainz, Judit; Fontenay, Gerald V; Kwon, Youngho; Leung, Stanley G; Lu, Lucy; Jensen, Ryan B; Chazin, Walter J; Wiese, Claudia; Sung, Patrick

Published In Mol Cell, (2015 Jul 16)

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.

PubMed ID: 26145171 Exiting the NIEHS site

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*

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