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Findings suggest need for new view of p53 cancer protein's interaction with DNA

PHILADELPHIA Perhaps the most commonly mutated of all cancer-linked genes is the gene for a tumor suppressor called p53. Scientists estimate that at least half of human cancers involve mutant p53. In the course of performing its regular duties, the normal p53 protein binds to DNA, and a number of cancer-linked p53 mutations affect the DNA-binding region of the p53 protein.

But precisely how does the p53 protein bind to DNA? Since DNA binding is crucial to the protein's usual function, the answer to this question is key to drug development efforts aimed at countering the effects of p53 mutations. Scientists thought that they had a good window on the p53 protein's interactions with DNA from structural studies that showed a single copy of the protein bound to DNA in a particular conformation.

Now a team of researchers from The Wistar Institute, the Memorial Sloan-Kettering Cancer Center, and the Howard Hughes Medical Institute report on new structural studies that will likely lead scientists to revise their views of how the p53 protein binds to DNA. The findings appear in today's issue of the journal Structure.

"Mutant forms of p53 in human cancer are often defective in their binding to DNA, and a number of groups are trying to develop drugs that might treat cancer by restoring the DNA-binding activity of these mutants," says Thanos D. Halazonetis, D.D.S., Ph.D., associate professor in the molecular and cellular oncogenesis program at Wistar and senior author on the Structure study. "A full understanding of precisely how p53 binds to DNA is essential for this work, however. Our studies suggest that we may need to adjust the existing model of how p53 binds to DNA."

Taking advantage of the fact that evolution commonly conserves vital proteins from species to species, Halazonetis and his colleagues solved the structure of the binding region of a protein called Cep-1 from C. elegans, a roundworm, and compared it to the binding region of hum
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Contact: Franklin Hoke
hoke@wistar.upenn.edu
215-898-3716
The Wistar Institute
14-Jul-2004


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