Journal
MOLECULAR CELL
Volume 59, Issue 2, Pages 176-187Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.05.032
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Funding
- US National Institutes of Health [ES015252, ES007061, CA168635, CA92584, ES021454, GM65484]
- NSF [0922862]
- NIH [S10 RR025677]
- Vanderbilt University
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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.
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