Anticancer Protein Locks onto DNA

Scientists now have a toehold on a slippery problem in cancer biology: the action of BRCA1, the gene most likely to be mutated in inherited breast cancer.

In its normal form, the gene encodes a tumor-suppressing protein, BRCA1. Previous genetic studies suggested that this protein protects against cancer by aiding in the repair of damaged DNA (SN: 4/15/00, p. 247). Now, a team of microbiologists led by Tanya T. Paull of the University of Texas in Austin has observed directly what BRCA1 is up to. The protein can seek out and attach to damaged DNA, the researchers report in the May 22 Proceedings of the National Academy of Sciences.

The role of BRCA1 in cancer suppression has been “like a black box,” says Jeffrey D. Parvin of Harvard University, who wrote a commentary that accompanies the report. “Inside that black box is a machine. This [finding] gives you an idea of one of the gears in that machine.”

Researchers in 1994 first recognized the link between an abnormal form of BRCA1 and inherited breast cancer (SN: 9/24/94, p. 197). Later, others found the flawed gene in some women without any family history of the disease (SN: 4/8/95, p. 213). Scientists now estimate that mutations of BRCA1 account for about 50 percent of all inherited breast cancers. Almost all families with a history of both ovarian and breast cancers carry the mutated gene.

The normal BRCA1 gene seems to have roles beyond cancer prevention. For instance, it may regulate nervous system development. Mice without any copies of the gene have no brain or a spine that doesn’t seal, and they die before birth (SN: 2/3/96, p. 69).

“The action of BRCA1 is clearly a complicated story,” says study coauthor Martin Gellert of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

Recent genetic evidence supports a role for BRCA1 in DNA repair, says Paull. For example, mice deficient in the protein have high rates of DNA mutations after exposure to radiation, which suggests that their damaged DNA isn’t being fixed.

Also, BRCA1 in mammalian genomes sits near other repair genes, and its protein interacts with what Gellert calls “a slew” of other proteins involved in DNA repair. “There is sort of guilt by association,” Paull says.

None of the previous evidence proved that BRCA1 has a direct role in genetic maintenance, says Parvin. It hadn’t been clear, for example, whether BRCA1 actually gets its hands dirty in gene-repair jobs or simply orchestrates the actions of other repair proteins.

“It could have been that BRCA1 binds to proteins that bind to DNA. There’s a lot of piggybacking,” Parvin notes.

To nail down BRCA1’s action, the researchers purified copies of the protein. In a test tube, they allowed the protein to bind with double strands of DNA. These had structures that mimic genetic damage, such as a Y-shaped branch or a nicked strand that causes a length of DNA to flap freely, explains Gellert.

In their experiments, the researchers report, the protein sought out and directly attached to the unusual DNA structures. In another experiment, BRCA1 worked with other proteins and bound multiple strands of DNA together, an activity that could be useful in repair.

Which of these activities observed in the test tube might actually occur in living cells remains to be seen, says Gellert.

The evidence indicates that BCRA1 is a hands-on participant in gene repair, notes Parvin. “I always thought that it was [only] indirectly involved in DNA repair, so I’m surprised.”