CHEMICAL & ENGINEERING
NEWS OF THE WEEK SEPTEMBER 16, 2002 - EDITED BY RUDY M. BAUM AND LOUISA WRAY DALTON
SCIENCE
BRCA2 DOES DNA DAMAGE CONTROL Structure of key breast cancer protein confirms its role in DNA repair
M
OST 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 D N A repair and paving the way for elucidation of its precise function in tumorigenesis [5aence, 297,1837 (2002)}. Since the discovery of BRCA2 in the mid-1990s, mounting circumstantial evidence has led scientists to suggest that BRCA2 functions to keep the genome free of damage, thereby keeping cancer at bay Its precise cellular role, however, has remained elusive. A team led by Howard Hughes Medical Institute investigator and structural biologist Nikola P. Pavletich presents structural and biochemical evidence that BRCA2 protects cells' genomic information by helping to repair double-strand breaks in DNA. The work "demonstrates the power of structural analysis to illuminate protein function," says biochemist StephenJ. 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, HTTP://PUBS.ACS.ORG/CEN
the team produced a three-dimensional picture of an 8 0 0 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-A-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 D N A . 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-A-resolution crystal structure of a similar portion of BRCA2 with a short piece of single-stranded D N A shows that BRCA2's oligonucleotide-binding domains bind to single-stranded D N A just like other oligonucleotide-binding domains do. Because regions of singlestranded D N A 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 D N A double-strand breaks. They confirmed in an in vitro biochemical assay that, in fact, it does. But D N A binding may not be the whole story Although some
CAUGHT IN THE ACT The crystal structure of the tumor suppressor BRCA2 (pink ribbon) bound to single-stranded DNA (bases shown in cyan) implicates BRCA2 in binding the single-stranded and doublestranded DNA substrates involved in repair of DNA double-strand breaks. BRCA2 localizes to distinct regions (pink dots) in nuclei of cells, shown in the background, where DNA repair is thought to occur. patients with hereditary breast cancer have defects in BRCA2's D N A 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.—AMANDA YARNELL
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