2014
DOI: 10.1038/nsmb.2899
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Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor

Abstract: Mutations in BRCA2 increase susceptibility to breast, ovarian and prostate cancers. The product of human BRCA2, BRCA2 protein, plays a key role in the repair of DNA double strand breaks and interstrand crosslinks 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 … Show more

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Cited by 102 publications
(135 citation statements)
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“…However, a scenario where the DNA damage response leads to coordinated activation of several simultaneous pathways that ensure faithful and efficient recombination is more likely. BRCA2 has been shown to diffuse in the nucleus together with RAD51, delivering it to the sites of DNA damage (52), with each BRCA2 binding four to five RAD51 monomers and promoting the filament nucleation (36,53). Phosphorylation of RAD51 may then ensure the filament growth on the RPA-coated ssDNA, because the RAD51 focus formation is reduced in c-Abl −/− cells (20).…”
Section: Discussionmentioning
confidence: 99%
“…However, a scenario where the DNA damage response leads to coordinated activation of several simultaneous pathways that ensure faithful and efficient recombination is more likely. BRCA2 has been shown to diffuse in the nucleus together with RAD51, delivering it to the sites of DNA damage (52), with each BRCA2 binding four to five RAD51 monomers and promoting the filament nucleation (36,53). Phosphorylation of RAD51 may then ensure the filament growth on the RPA-coated ssDNA, because the RAD51 focus formation is reduced in c-Abl −/− cells (20).…”
Section: Discussionmentioning
confidence: 99%
“…BRCA2 is a huge protein that encompasses 3418 amino acids in humans. Shahid and coworkers recently revealed the structure of full-length BRCA2 as being a dimer, using cryo-EM 3D reconstruction (Shahid et al 2014). The sequence conservation among BRCA2 orthologs among various species is mostly limited to the N-terminal, the middle part, and the C-terminal regions; therefore, these regions may be more important for genome maintenance (Takata et al 2002).…”
Section: General Featuresmentioning
confidence: 99%
“…The data of the Western blot analyses show the expression of DBD fused to BRC3-4, AD fused to RAD51 and β-actin after their co-transfection in a parallel experiment. Total T-K 63 55 35 73 70 296 T-R 13 40 54 29 12 148 P-K 6 5 11 0 6 28 P-R 0 0 0 0 0 0 Total 82 100 100 102 88 472 a Number of haplotypes in each breed b T1425P and K1435R polymorphisms study suggests that BRCA2 forms dimers, in which each BRCA2 interacts with four RAD51 via respective BRC repeats, and acts as a molecular chaperone for RAD51-DNA filament assembly (13). Because BRC1-4 exhibit higher affinity for RAD51 than do BRC5-8 (2, 3), BRC1-4 may play essential roles in BRCA2 dimers.…”
mentioning
confidence: 99%