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PMID:25282148

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Citation

Shahid, T, Soroka, J, Kong, E, Malivert, L, McIlwraith, MJ, Pape, T, West, SC and Zhang, X (2014) Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor. Nat. Struct. Mol. Biol. 21:962-968

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 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.

Links

PubMed PMC4222816 Online version:10.1038/nsmb.2899

Keywords

BRCA2 Protein/chemistry; BRCA2 Protein/genetics; BRCA2 Protein/metabolism; DNA Breaks, Double-Stranded; DNA Repair; DNA, Single-Stranded/chemistry; DNA, Single-Stranded/genetics; DNA, Single-Stranded/metabolism; Gene Expression; HeLa Cells; Homologous Recombination; Humans; Models, Molecular; Protein Conformation; Protein Multimerization; Rad51 Recombinase/chemistry; Rad51 Recombinase/genetics; Rad51 Recombinase/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BRCA2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q06609

F

Seeded From UniProt

complete

HUMAN:RAD51

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P51587

F

Seeded From UniProt

complete

HUMAN:BRCA2

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P51587

F

Seeded From UniProt

complete

HUMAN:RAD51

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q06609

F

Seeded From UniProt

complete

Notes

See also

References

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