Scientists have solved the ornery crystal structure of a protein that, when mutated, is involved in breast cancer. The study confirms the protein's role in DNA repair and should help elucidate how DNA repair can break down and lead to cancer. But it leaves plenty of thorny questions unanswered.
For many years, scientists have known that mutations in the genes coding for the proteins BRCA1 and BRCA2 increase risk of breast and ovarian cancer by 30% to 70% and account for half of all hereditary cases of the diseases. They have also had several clues that the proteins are involved in DNA repair: They consort with known repair proteins, and mutant versions make cells virtually unable to repair DNA when both strands of the double helix are broken. Poor repair of these "double-strand breaks" can activate cancer-causing genes or inactivate tumor-suppressor genes. But BRCA2 is a large, fussy molecule, difficult to isolate and characterize with x-ray crystallography. So nobody knew its structure or whether it directly contacts DNA during repair or, like BRCA1, plays an indirect role.
To profile BRCA2, researchers stabilized it by combining it with DSS1, another repair protein. This let them describe the structure of its tail end, which provided near-ironclad evidence that BRCA2 gets down and dirty with DNA. It contains three binding sites for single-stranded DNA and has a so-called tower domain: a bundle of helices that resembles the structures other organisms use to bind double-stranded DNA. The researchers also showed that BRCA2 helps other repair proteins using a template to turn a single-stranded DNA fragment into a longer double strand, a process integral to the repair of double-strand breaks. The team, led by Nikola Pavletich of the Memorial Sloan-Kettering Cancer Center in New York City, reports the findings in the 13 September issue of Science.
The study "provides a striking view of the protein and the way in which it functions as a caretaker of the genome," says oncologist Bert Vogelstein of Johns Hopkins University School of Medicine in Baltimore, Maryland. It also brings up crucial questions for future research: Scientists still don't know how particular mutations cause cancer, why they lead to cancer in some tissues and not others, or what might be done to counteract the mutations.