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

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

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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 invivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically andfunctionally 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.

Original languageEnglish (US)
Pages (from-to)176-187
Number of pages12
JournalMolecular Cell
Volume59
Issue number2
DOIs
StatePublished - Jul 16 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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