title: Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry.
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 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.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Departments of Biochemistry and Chemistry, and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Sivaraja
authors.initials: S
authors.lastname: Vaithiyalingam
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: San Filippo
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Maranon
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Jimenez-Sainz
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Fontenay
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Youngho
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Leung
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Jensen
authors.affiliation: Departments of Biochemistry and Chemistry, and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: walter.chazin@vanderbilt.edu.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wiese
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: patrick.sung@yale.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
mesh_terms: D019943:Amino Acid Substitution; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D002460:Cell Line; D005260:Female; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D008954:Models, Biological; D018716:Molecular Mimicry; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051716:Replication Protein A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D021122:Protein Subunits; C497167:RPA1 protein, human; D011994:Recombinant Proteins; D051716:Replication Protein A; C484606:SEM1 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D046988:Proteasome Endopeptidase Complex