Purified human BRCA2 stimulates RAD51-mediated recombination
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The purification of full-length BRCA2 is reported and it is shown that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA).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.read more
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References
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Journal ArticleDOI
Genetic instabilities in human cancers
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Journal ArticleDOI
Identification of the breast cancer susceptibility gene BRCA2
Richard Wooster,Graham R. Bignell,Johnathan M. Lancaster,Sally Swift,Sheila Seal,Jonathon Mangion,N. Collins,Simon G. Gregory,Curtis Gumbs,Gos Micklem +9 more
TL;DR: The identification of a gene in which six different germline mutations in breast cancer families that are likely to be due to BRCA2 are detected, and results indicate that this is the BRC a2 gene.
Journal ArticleDOI
Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2
Shyam K. Sharan,Masami Morimatsu,Masami Morimatsu,Urs Albrecht,Dae-Sik Lim,Eva Regel,Christopher Dinh,Arthur T. Sands,Gregor Eichele,Paul Hasty,Allan Bradley +10 more
TL;DR: Developmental arrest in Brca2-deficient embryos, their radiation sensitivity, and the association of Brca1 with Rad51 indicate that Brca 2 may be an essential cofactor in the Rad51-dependent DNA repair of double-strand breaks, thereby explaining the tumour-suppressor function of BrCA2.
Journal ArticleDOI
Erratum: Identification of the breast cancer susceptibility gene BRCA2
Richard Wooster,Graham R. Bignell,Jonathan Lancaster,Sally Swift,Sheila Seal,Jonathan Mangion,N. Collins,Simon G. Gregory,Curtis Gumbs,Gos Michlem,Rita Barfoot,Rifat Hamoudi,Sandeep Patel,Catherine M. Rice,Patrick J. Biggs,Yasmin Hashim,Amanda Smith,Frances Connor,Adelgeir Arason,Julius Gudmundsson,David Ficenec,David P. Kelsell,D Ford,Patricia N. Tonin,D. Timothy Bishop,Nigel K. Spurr,Bruce A.J. Ponder,Rosalind A. Eeles,Julian Peto,Peter Devilee,Cees J. Cornelisse,Henry T. Lynch,Steven A. Narod,Gilbert M. Lenoir,Valdgardur Egilsson,Rosa Bjork Barkadottir,Douglas F. Easton,David R. Bentley,P. Andrew Futreal,Alan Ashworth,Michael R. Stratton +40 more
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BRCA2 is required for homology-directed repair of chromosomal breaks.
TL;DR: It is proposed that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and, possibly, tumorigenesis, through lack of repair or misrepair of DNA damage.