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Initial sensor for p53 tumor-suppressing pathway identified

PHILADELPHIA - DNA breaks from radiation, toxic chemicals, or other environmental causes occur routinely in cells and, unless promptly and properly repaired, can lead to cancer-causing mutations. When the breaks cannot be repaired, and the cell is vulnerable to becoming cancerous, critical backup protection governed by the p53 protein kicks in. This protein is the end of the line in a vital signaling cascade that triggers cells with fatally damaged DNA to self-destruct so that they cannot cause cancer.

The importance of the p53 pathway in preventing cancer cannot be overstated. Scientists know, for example, that in the majority of human cancers the p53 pathway has been disabled. Despite the crucial nature of the p53 tumor-suppressor pathway, the answer to a central question has evaded researchers for years: How is the p53 pathway alerted to the presence of DNA breaks in the cell in the first place? If p53 lies at the end of the line in this pathway, what molecule is at the front, and how does it do its job?

In a new study led by researchers at The Wistar Institute, the sensor protein that identifies DNA breaks and activates the p53 cell-death program has been identified. Additionally, structural analysis of the protein and its interactions with DNA has revealed the specific mechanism by which the protein detects the breaks. The study will be published November 3 in the advance online edition of the journal Nature.

"We had been studying this protein for some time, and we knew it was important in the cellular response to DNA breaks," says Thanos D. Halazonetis, D.D.S., Ph.D., a professor in the gene expression and regulation program at The Wistar Institute and senior author on the Nature study. "Now, we know it is the initial sensor for the p53 tumor-suppressor pathway - it is responsible for detecting DNA breaks - and we also have a good idea how it works."

According to Halazonetis, the protein, known as 53BP1, recognizes a molecular s
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Contact: Franklin Hoke
hoke@wistar.upenn.edu
215-898-3716
The Wistar Institute
3-Nov-2004


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