BRCA2 regulates DMC1-mediated recombination through the BRC repeats

Juan S. Martinez, Catharina Von Nicolai, Taeho Kim, Åsa Ehlén, Alexander V. Mazin, Stephen C. Kowalczykowski, Aura Carreira

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

In somatic cells, BRCA2 is needed for RAD51-mediated homologous recombination. The meiosis-specific DNA strand exchange protein, DMC1, promotes the formation of DNA strand invasion products (joint molecules) between homologous molecules in a fashion similar to RAD51. BRCA2 interacts directly with both human RAD51 and DMC1; in the case of RAD51, this interaction results in stimulation of RAD51-promoted DNA strand exchange. However, for DMC1, little is known regarding the basis and functional consequences of its interaction with BRCA2. Here we report that human DMC1 interacts directly with each of the BRC repeats of BRCA2, albeit most tightly with repeats 1-3 and 6-8. However, BRC1-3 bind with higher affinity to RAD51 than to DMC1, whereas BRC6-8 bind with higher affinity to DMC1, providing potential spatial organization to nascent filament formation. With the exception of BRC4, each BRC repeat stimulates joint molecule formation by DMC1. The basis for this stimulation is an enhancement of DMC1-ssDNA complex formation by the stimulatory BRC repeats. Lastly, we demonstrate that full-length BRCA2 protein stimulates DMC1-mediated DNA strand exchange between RPA-ssDNA complexes and duplex DNA, thus identifying BRCA2 as a mediator of DMC1 recombination function. Collectively, our results suggest unique and specialized functions for the BRC motifs of BRCA2 in promoting homologous recombination in meiotic and mitotic cells.

Original languageEnglish (US)
Pages (from-to)3515-3520
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number13
DOIs
StatePublished - Mar 29 2016

Keywords

  • BRCA2
  • DMC1
  • Mediator
  • Meiosis
  • RAD51

ASJC Scopus subject areas

  • General

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    Martinez, J. S., Von Nicolai, C., Kim, T., Ehlén, Å., Mazin, A. V., Kowalczykowski, S. C., & Carreira, A. (2016). BRCA2 regulates DMC1-mediated recombination through the BRC repeats. Proceedings of the National Academy of Sciences of the United States of America, 113(13), 3515-3520. https://doi.org/10.1073/pnas.1601691113