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SCIENCE
Most hereditary breast and ovarian cancers result from mutations in the tumor suppressor proteins BRCA1 and BRCA2. Scientists at Memorial Sloan-Kettering Cancer Center have solved the structure of part of BRCA2, cementing the protein's previously proposed role in DNA repair and paving the way for elucidation of its precise function in tumorigenesis [Science, 297, 1837 (2002)].
The work "demonstrates the power of structural analysis to illuminate protein function," says biochemist Stephen J. Elledge of Baylor College of Medicine. Ashok R. Venkitaraman, a cancer researcher at the University of Cambridge, agrees, noting that the structure provides "a basis for understanding why cells that lack BRCA2 are predisposed to becoming cancer cells." Using X-ray crystallography, the team produced a three-dimensional picture of an 800-amino-acid portion of the more than 3,000 residue BRCA2 protein. Despite BRCA2's large size, it shares no sequence homology with any known protein. So the researchers were surprised to find that parts of the 3.1-Å-resolution structure look just like protein motifs known to bind DNA. The structure shows a helical tower capped with a three-helix DNA-binding domain similar to those found in certain proteins that bind in the major groove of double-stranded DNA. At the base of the tower is a chain of three oligonucleotide-binding domains similar to those found in most proteins that bind to single-stranded DNA. A second, 3.5-Å-resolution crystal structure of a similar portion of BRCA2 with a short piece of single-stranded DNA shows that BRCA2's oligonucleotide-binding domains bind to single-stranded DNA just like other oligonucleotide-binding domains do. Because regions of single-stranded DNA are created when double-strand breaks occur in the genome, this combination of structural features led the team to suspect that BRCA2 plays a role in the repair of DNA double-strand breaks. They confirmed in an in vitro biochemical assay that, in fact, it does. But DNA binding may not be the whole story. Although some patients with hereditary breast cancer have defects in BRCA2's DNA binding regions, other patients exhibit defects in additional regions of the protein--so BRCA2's function is likely to be more complicated. The structure will allow biochemists to design experiments to determine the precise functions of the BRCA2 protein as well as to study the effects of cancer-associated mutations on BRCA2 function, Elledge says. "But it won't immediately translate into new breast cancer therapies," he cautions. |
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