Initial Sensor for p53 Tumor-Suppressing Pathway Identified

Initial Sensor for p53 Tumor-Suppressing Pathway Identified

November 2, 2004

(PHILADELPHIA - November 3, 2004) - 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 detects 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 site usually hidden within the DNA-packaging structure called chromatin, which makes up our chromosomes. Chromatin consists of DNA coiled around the edges of molecules called histones to form disk-shaped entities called nucleosomes. The nucleosomes themselves, then, are tightly packed together - possibly like a stack of coins, Halazonetis suggests - to form the dense chromatin. When all is as it should be with the DNA, a target site for 53BP1 lies at the center of each of the stacked nucleosome disks and is not available for binding.

"But if you have a DNA break, you can imagine that the nucleosomes might unravel and the stacking of the nucleosomes fall apart, exposing the site that 53BP1 recognizes," Halazonetis says. "This is the model we are proposing for how cells sense the presence of DNA breaks to activate the p53 pathway."

The lead author on the Nature study is Yentram Huyen at The Wistar Institute. Other Wistar-based coauthors are Omar Zgheib, Richard A. DiTullio, Jr., Vassilis G. Gorgoulis, M.D., Ph.D., Panayotis Zacharatos, Ph.D., Tom J. Petty, Emily A. Sheston, Hestia S. Mellert, and Elena S. Stavridi, Ph.D., who oversaw the crystallographic analysis of the 53BP1 structure. Huyen, Zgheib, DiTullio, and Petty are also affiliated with the University of Pennsylvania, as is senior author Halazonetis; Gorgoulis and Zacharatos are additionally affiliated with the University of Athens, Greece. Funding for the study was provided by the National Cancer Institute, one of the National Institutes of Health.

The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.

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