BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure Journal Article
| Authors: | Yang, H.; Jeffrey, P. D.; Miller, J.; Kinnucan, E.; Sun, Y.; Thomä, N. H.; Zheng, N.; Chen, P. L.; Lee, W. H.; Pavletich, N. P. |
| Article Title: | BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure |
| Abstract: | Mutations in the BRCA2 (breast cancer susceptibility gene 2) tumor suppressor lead to chromosomal instability due to defects in the repair of double-strand DNA breaks (DSBs) by homologous recombination, but BRCA2's role in this process has been unclear. Here, we present the 3.1 angstrom crystal structure of a ∼90-kilodalton BRCA2 domain bound to DSS1, which reveals three oligonucleotide-binding (OB) folds and a helix-turn-helix (HTH) motif. We also (i) demonstrate that this BRCA2 domain binds single-stranded DNA, (ii) present its 3.5 angstrom structure bound to oligo(dT)9′ (iii) provide data that implicate the HTH motif in dsDNA binding, and (iv) show that BRCA2 stimulates RAD51-mediated recombination in vitro. These findings establish that BRCA2 functions directly in homologous recombination and provide a structural and biochemical basis for understanding the loss of recombination-mediated DSB repair in BRCA2-associated cancers. |
| Keywords: | gene mutation; mutation; dna-binding proteins; protein conformation; protein domain; protein motif; proteins; chromosome; dna recombination; animals; mice; dna repair; cancer susceptibility; proteasome endopeptidase complex; breast cancer; biology; protein dna binding; gene function; in vitro study; brca2 protein; dna strand breakage; oncogene; tumor suppressor gene; dna; double stranded dna; amino acid sequence; molecular sequence data; tumors; recombination, genetic; genes, brca2; chromosomal instability; crystal structure; dna structure; hydrogen bonding; crystallography, x-ray; protein structure, tertiary; binding sites; rats; dna, single-stranded; protein folding; dna binding; oligonucleotide; protein structure, secondary; mutagenesis; rad51 recombinase; hydrophobicity; helix loop helix protein; cancer; humans; priority journal; article; helix-turn-helix motifs |
| Journal Title: | Science |
| Volume: | 297 |
| Issue: | 5588 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2002-01-01 |
| Start Page: | 1837 |
| End Page: | 1848 |
| Language: | English |
| DOI: | 10.1126/science.297.5588.1837 |
| PUBMED: | 12228710 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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