The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction Journal Article
| Authors: | Yang, H.; Li, Q.; Fan, J.; Holloman, W. K.; Pavletich, N. |
| Article Title: | The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction |
| Abstract: | The BRCA2 tumour suppressor is essential for the error-free repair of double-strand breaks (DSBs) in DNA by homologous recombination. This is mediated by RAD51, which forms a nucleoprotein filament with the 3′ overhanging single-stranded DNA (ssDNA) of the resected DSB, searches for a homologous donor sequence, and catalyses strand exchange with the donor DNA. The 3,418-amino-acid BRCA2 contains eight ∼30-amino-acid BRC repeats that bind RAD51 (refs 5,6) and a ∼700-amino-acid DBD domain that binds ssDNA. The isolated BRC and DBD domains have the opposing effects of inhibiting and stimulating recombination, respectively, and the role of BRCA2 in repair has been unclear. Here we show that a full-length BRCA2 homologue (Brh2) stimulates Rad51-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA (dsDNA) and ssDNA, with strict specificity for the 3′ overhang polarity of a resected DSB. These results establish a BRCA2 function in RAD51-mediated DSB repair and explain the loss of this repair capacity in BRCA2-associated cancers. |
| Keywords: | unclassified drug; dna binding protein; genetics; dna-binding proteins; nonhuman; protein conformation; proteins; metabolism; dna damage; homologous recombination; dna repair; biology; brca2 protein; dna strand breakage; tumor suppressor gene; chemistry; dna; double stranded dna; genetic engineering; tumors; escherichia coli; dna, viral; dna sequence; amino acids; single stranded dna; conformation; dna, single-stranded; nucleic acid conformation; sequence homology; tumor suppressor protein; adenosine triphosphatase; adenosine triphosphatases; streptavidin; autoradiography; replication protein a; fungal protein; rad51 protein; polyacrylamide gel electrophoresis; stoichiometry; biotin; crossing over; crossing over, genetic; nucleation; rad51 recombinase; virus dna; ustilago maydis; fungal proteins; filament formation; functions; negibacteria; error-free repair; single-stranded dna (ssdna); anazolene sodium; brh2 protein; nucleoprotein; bacteriophage phi x 174; ustilago |
| Journal Title: | Nature |
| Volume: | 433 |
| Issue: | 7026 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2005-02-10 |
| Start Page: | 653 |
| End Page: | 657 |
| Language: | English |
| DOI: | 10.1038/nature03234 |
| PUBMED: | 15703751 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 146" - "Export Date: 24 October 2012" - "CODEN: NATUA" - "Source: Scopus" |
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