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BRCA2 regulates DMC1-mediated recombination through the BRC repeats
Journal article   Open access

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 and Aura Carreira
Proceedings of the National Academy of Sciences - PNAS, v 113(13), pp 3515-3520
29 Mar 2016
DOI: https://doi.org/10.1073/pnas.1601691113
PMID: 26976601
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1073/pnas.1601691113View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Adenosine Triphosphate - metabolism BRCA2 Protein - chemistry BRCA2 Protein - genetics BRCA2 Protein - metabolism Cell Cycle Proteins - chemistry Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism DNA, Single-Stranded - genetics DNA, Single-Stranded - metabolism DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Homologous Recombination Humans Hydrolysis In Vitro Techniques Meiosis - genetics Models, Biological Models, Molecular Protein Interaction Domains and Motifs Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Repetitive Sequences, Amino Acid Replication Protein A - genetics Replication Protein A - metabolism
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.

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Domestic collaboration
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Web of Science research areas
Biochemistry & Molecular Biology
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