Purified human BRCA2 stimulates RAD51-mediated recombination

Ryan B. Jensen, Aura Carreira, Stephen C. Kowalczykowski

Research output: Contribution to journalArticle

332 Citations (Scopus)

Abstract

Mutation of the breast cancer susceptibility gene, BRCA2, leads to breast and ovarian cancers. Mechanistic insight into the functions of human BRCA2 has been limited by the difficulty of isolating this large protein (3,418 amino acids). Here we report the purification of full-length BRCA2 and show that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). BRCA2 acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51 ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. Our findings show that BRCA2 is a key mediator of homologous recombination, and they provide a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations, which lead to chromosomal instability and cancer.

Original languageEnglish (US)
Pages (from-to)678-683
Number of pages6
JournalNature
Volume467
Issue number7316
DOIs
StatePublished - Oct 7 2010

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Single-Stranded DNA
Genetic Recombination
Replication Protein A
Breast Neoplasms
Recombinational DNA Repair
Chromosomal Instability
Mutation
Neoplasm Genes
Homologous Recombination
DNA Repair
Ovarian Neoplasms
Hydrolysis
Adenosine Triphosphate
Amino Acids
DNA
Neoplasms
Proteins

ASJC Scopus subject areas

  • General

Cite this

Jensen, R. B., Carreira, A., & Kowalczykowski, S. C. (2010). Purified human BRCA2 stimulates RAD51-mediated recombination. Nature, 467(7316), 678-683. https://doi.org/10.1038/nature09399

Purified human BRCA2 stimulates RAD51-mediated recombination. / Jensen, Ryan B.; Carreira, Aura; Kowalczykowski, Stephen C.

In: Nature, Vol. 467, No. 7316, 07.10.2010, p. 678-683.

Research output: Contribution to journalArticle

Jensen, RB, Carreira, A & Kowalczykowski, SC 2010, 'Purified human BRCA2 stimulates RAD51-mediated recombination', Nature, vol. 467, no. 7316, pp. 678-683. https://doi.org/10.1038/nature09399
Jensen RB, Carreira A, Kowalczykowski SC. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature. 2010 Oct 7;467(7316):678-683. https://doi.org/10.1038/nature09399
Jensen, Ryan B. ; Carreira, Aura ; Kowalczykowski, Stephen C. / Purified human BRCA2 stimulates RAD51-mediated recombination. In: Nature. 2010 ; Vol. 467, No. 7316. pp. 678-683.
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