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Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor

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 structur...

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Autores principales: Shahid, Taha, Soroka, Joanna, Kong, Eric, Malivert, Laurent, McIlwraith, Michael J., Pape, Tillman, West, Stephen C., Zhang, Xiaodong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222816/
https://www.ncbi.nlm.nih.gov/pubmed/25282148
http://dx.doi.org/10.1038/nsmb.2899
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author Shahid, Taha
Soroka, Joanna
Kong, Eric
Malivert, Laurent
McIlwraith, Michael J.
Pape, Tillman
West, Stephen C.
Zhang, Xiaodong
author_facet Shahid, Taha
Soroka, Joanna
Kong, Eric
Malivert, Laurent
McIlwraith, Michael J.
Pape, Tillman
West, Stephen C.
Zhang, Xiaodong
author_sort Shahid, Taha
collection PubMed
description 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 electron microscopy 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.
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spelling pubmed-42228162015-05-01 Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor Shahid, Taha Soroka, Joanna Kong, Eric Malivert, Laurent McIlwraith, Michael J. Pape, Tillman West, Stephen C. Zhang, Xiaodong Nat Struct Mol Biol Article 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 electron microscopy 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. 2014-10-05 2014-11 /pmc/articles/PMC4222816/ /pubmed/25282148 http://dx.doi.org/10.1038/nsmb.2899 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Shahid, Taha
Soroka, Joanna
Kong, Eric
Malivert, Laurent
McIlwraith, Michael J.
Pape, Tillman
West, Stephen C.
Zhang, Xiaodong
Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor
title Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor
title_full Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor
title_fullStr Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor
title_full_unstemmed Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor
title_short Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor
title_sort structure and mechanism of action of the brca2 breast cancer tumor suppressor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222816/
https://www.ncbi.nlm.nih.gov/pubmed/25282148
http://dx.doi.org/10.1038/nsmb.2899
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