title: BRCA2 regulates DMC1-mediated recombination through the BRC repeats.
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.
authors.affiliation: Genotoxic Stress and Cancer Unit, Institut Curie, Research Center, Orsay 91405, France; CNRS UMR3348, Centre Universitaire, Orsay 91405, France;
authors.forename: Juan S
authors.initials: JS
authors.lastname: Martinez
authors.affiliation: Genotoxic Stress and Cancer Unit, Institut Curie, Research Center, Orsay 91405, France; CNRS UMR3348, Centre Universitaire, Orsay 91405, France;
authors.forename: Catharina
authors.initials: C
authors.lastname: von Nicolai
authors.affiliation: Departments of Microbiology and Molecular Genetics and of Molecular and Cellular Biology, University of California, Davis, CA 95616-8665;
authors.forename: Taeho
authors.initials: T
authors.lastname: Kim
authors.affiliation: Genotoxic Stress and Cancer Unit, Institut Curie, Research Center, Orsay 91405, France; CNRS UMR3348, Centre Universitaire, Orsay 91405, France;
authors.forename: Åsa
authors.initials: Å
authors.lastname: Ehlén
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102-1192.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mazin
authors.affiliation: Departments of Microbiology and Molecular Genetics and of Molecular and Cellular Biology, University of California, Davis, CA 95616-8665; sckowalczykowski@ucdavis.edu aura.carreira@curie.fr.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Kowalczykowski
authors.affiliation: Genotoxic Stress and Cancer Unit, Institut Curie, Research Center, Orsay 91405, France; CNRS UMR3348, Centre Universitaire, Orsay 91405, France; sckowalczykowski@ucdavis.edu aura.carreira@curie.fr.
authors.forename: Aura
authors.initials: A
authors.lastname: Carreira
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D024682:BRCA2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D059765:Homologous Recombination; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008540:Meiosis / Q000235:genetics; D008954:Models, Biological; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D051716:Replication Protein A / Q000235:genetics / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D051716:Replication Protein A; D000255:Adenosine Triphosphate; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C074556:DMC1 protein, human
keywords: BRCA2; DMC1; RAD51; mediator; meiosis