BRCA2-MAGE-D1 complex / negative regulation of mammary gland epithelial cell proliferation / presynaptic intermediate filament cytoskeleton / mitotic recombination-dependent replication fork processing / cellular response to camptothecin / chromosome organization involved in meiotic cell cycle / establishment of protein localization to telomere / telomere maintenance via telomere lengthening / positive regulation of DNA ligation / Impaired BRCA2 translocation to the nucleus ...BRCA2-MAGE-D1 complex / negative regulation of mammary gland epithelial cell proliferation / presynaptic intermediate filament cytoskeleton / mitotic recombination-dependent replication fork processing / cellular response to camptothecin / chromosome organization involved in meiotic cell cycle / establishment of protein localization to telomere / telomere maintenance via telomere lengthening / positive regulation of DNA ligation / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / double-strand break repair involved in meiotic recombination / nuclear ubiquitin ligase complex / cellular response to hydroxyurea / replication-born double-strand break repair via sister chromatid exchange / lateral element / telomere maintenance via recombination / DNA recombinase assembly / histone H4 acetyltransferase activity / histone H3 acetyltransferase activity / regulation of DNA damage checkpoint / mitotic recombination / Impaired BRCA2 binding to PALB2 / DNA strand invasion / HDR through MMEJ (alt-NHEJ) / gamma-tubulin binding / DNA strand exchange activity / reciprocal meiotic recombination / DNA repair complex / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / response to UV-C / oocyte maturation / Resolution of D-loop Structures through Holliday Junction Intermediates / single-stranded DNA helicase activity / inner cell mass cell proliferation / ATP-dependent DNA damage sensor activity / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / hematopoietic stem cell proliferation / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / regulation of double-strand break repair via homologous recombination / nuclear chromosome / female gonad development / replication fork processing / male meiosis I / DNA unwinding involved in DNA replication / Transcriptional Regulation by E2F6 / Presynaptic phase of homologous DNA pairing and strand exchange / centrosome duplication / response to X-ray / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / ATP-dependent activity, acting on DNA / interstrand cross-link repair / DNA polymerase binding / condensed chromosome / positive regulation of mitotic cell cycle / meiotic cell cycle / regulation of cytokinesis / condensed nuclear chromosome / secretory granule / male germ cell nucleus / cellular response to ionizing radiation / nucleotide-excision repair / response to gamma radiation / regulation of protein phosphorylation / double-strand break repair via homologous recombination / HDR through Homologous Recombination (HRR) / brain development / PML body / Meiotic recombination / cellular senescence / double-strand break repair / site of double-strand break / single-stranded DNA binding / spermatogenesis / double-stranded DNA binding / DNA recombination / protease binding / chromosome, telomeric region / mitochondrial matrix / DNA repair / centrosome / DNA damage response / chromatin binding / regulation of DNA-templated transcription / chromatin / nucleolus / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / enzyme binding / ATP hydrolysis activity / protein-containing complex / mitochondrion / nucleoplasm / ATP binding / identical protein binding Similarity search - Function
: / BRCA2, OB2 / BRCA2, OB3 / Tower domain / Breast cancer type 2 susceptibility protein, helical domain / BRCA2 helical domain superfamily / BRCA2, oligonucleotide/oligosaccharide-binding, domain 3 / Tower / BRCA2, helical / Tower ...: / BRCA2, OB2 / BRCA2, OB3 / Tower domain / Breast cancer type 2 susceptibility protein, helical domain / BRCA2 helical domain superfamily / BRCA2, oligonucleotide/oligosaccharide-binding, domain 3 / Tower / BRCA2, helical / Tower / Breast cancer type 2 susceptibility protein / BRCA2 repeat / BRCA2, OB1 / Breast cancer type 2 susceptibility protein / BRCA2 repeat / BRCA2, oligonucleotide/oligosaccharide-binding, domain 1 / BRCA2 repeat profile. / DNA recombination/repair protein Rad51 / DNA recombination and repair protein, RecA-like / DNA recombination and repair protein Rad51-like, C-terminal / Rad51 / DNA recombination and repair protein RecA, monomer-monomer interface / RecA family profile 2. / DNA recombination and repair protein RecA-like, ATP-binding domain / RecA family profile 1. / DNA repair Rad51/transcription factor NusA, alpha-helical / Helix-hairpin-helix domain / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Nucleic acid-binding, OB-fold / P-loop containing nucleoside triphosphate hydrolase Similarity search - Domain/homology
Journal: Nat Struct Mol Biol / Year: 2014 Title: Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor. Authors: Taha Shahid / Joanna Soroka / Eric Kong / Laurent Malivert / Michael J McIlwraith / Tillman Pape / Stephen C West / Xiaodong Zhang / Abstract: Mutations in BRCA2 increase susceptibility to breast, ovarian and prostate cancers. The product of human BRCA2, BRCA2 protein, has a key role in the repair of DNA double-strand breaks and interstrand ...Mutations in BRCA2 increase susceptibility to breast, ovarian and prostate cancers. The product of human BRCA2, BRCA2 protein, has a key role in the repair of DNA double-strand breaks and interstrand cross-links by RAD51-mediated homologous recombination. Here, we present a biochemical and structural characterization of full-length (3,418 amino acid) BRCA2, alone and in complex with RAD51. We show that BRCA2 facilitates nucleation of RAD51 filaments at multiple sites on single-stranded DNA. Three-dimensional EM reconstructions revealed that BRCA2 exists as a dimer and that two oppositely oriented sets of RAD51 molecules bind the dimer. Single-stranded DNA binds along the long axis of BRCA2, such that only one set of RAD51 monomers can form a productive complex with DNA and establish filament formation. Our data define the molecular mechanism by which this tumor suppressor facilitates RAD51-mediated homologous-recombinational repair.
History
Deposition
Sep 3, 2014
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Header (metadata) release
Sep 17, 2014
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Map release
Oct 8, 2014
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Update
Oct 8, 2014
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Current status
Oct 8, 2014
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Macromolecule #1: Breast cancer type 2 susceptibility protein
Macromolecule
Name: Breast cancer type 2 susceptibility protein / type: protein_or_peptide / ID: 1 / Name.synonym: BRCA2 / Number of copies: 2 / Oligomeric state: Dimer / Recombinant expression: Yes
Source (natural)
Organism: Homo sapiens (human) / synonym: Human / Location in cell: Nucleus
Molecular weight
Theoretical: 384 KDa
Recombinant expression
Organism: Homo sapiens (human) / Recombinant cell: HeLa
Sequence
UniProtKB: Breast cancer type 2 susceptibility protein / InterPro: Breast cancer type 2 susceptibility protein
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Macromolecule #2: DNA repair protein RAD51 homolog 1
Macromolecule
Name: DNA repair protein RAD51 homolog 1 / type: protein_or_peptide / ID: 2 / Name.synonym: HsRAD51 / Number of copies: 8 / Oligomeric state: Dimer of tetramers / Recombinant expression: Yes
Source (natural)
Organism: Homo sapiens (human) / synonym: Human / Location in cell: Nucleus
Molecular weight
Theoretical: 37 KDa
Recombinant expression
Organism: Escherichia coli (E. coli)
Sequence
UniProtKB: DNA repair protein RAD51 homolog 1
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Experimental details
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Structure determination
Method
negative staining
Processing
single particle reconstruction
Aggregation state
particle
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Sample preparation
Staining
Type: NEGATIVE Details: Grid with adsorbed protein was washed twice with water and negatively stained with 2% uranyl acetate solution before being blotted and air dried.
Grid
Details: Copper Quantifoil R2/2 holey carbon grids coated with continuous carbon, glow discharged in air.
Vitrification
Cryogen name: NONE / Instrument: OTHER
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Electron microscopy #1
Microscopy ID
1
Microscope
FEI/PHILIPS CM200FEG
Alignment procedure
Legacy - Astigmatism: Objective lens astigmatism was corrected at 150,000 times magnification.
Date
Dec 14, 2012
Image recording
Category: CCD / Film or detector model: TVIPS TEMCAM-F415 (4k x 4k) / Average electron dose: 40 e/Å2 / Bits/pixel: 16
Electron beam
Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 19.5 Å / Resolution method: OTHER / Software - Name: IMAGIC-5, Tigris Details: Final maps were calculated after a round of projection matching. Number images used: 6877
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