"Epstein-Barr virus (EBV) is one of the most common human viruses in the world and is strongly linked to certain b-cell cancers like Burkitt's lymphoma as well as the epithelial cell cancer, nasopharyngeal carcinoma. EBNA1 is a protein coded in the Epstein-Barr virus and suspected to play a role in the development of cancer," says Lori Frappier, professor in medical genetics and microbiology at U of T and senior author of a paper in the April 1 issue of Molecular Cell.
"This research shows how EBNA1 interferes with natural cell growth regulation by binding to a particular protein in cells, causing them to continue growing and therefore increasing the risk of becoming cancerous."
Frappier explains that all cells contain the two proteins - p53 and USP7 - that work together to regulate cell growth. P53 is an important protein whose level in the cell determines whether cells will continue to proliferate or stop dividing and die. USP7 is a protein that binds to p53 and makes it stable. Under those conditions, cells stop growing and die, which is a natural state of cell regulation. Once EBNA1 is introduced to cells, however, this protein interferes with natural cell regulation by binding to USP7 and preventing its interaction with the p53 protein.
"Normally, p53 levels will increase in response to certain problems in the cell such as damaged DNA and this stops the cell from proliferating. Through binding USP7, EBNA1 keeps the p53 levels low so cells will continue to divide when they shouldn't, which means they're now more likely to develop into cancer," Frappier says.
"All viruses known to be able to cause cancer, like the human papillomavirus that causes cervical cancer for example, have been shown to work through this p53 protein, but up until now, no one's ever found any regulation of p53 that's associated with the Epstein-Barr virus. That was surprising because all other viruses that stimulate cell proliferation do it through p53. The question was why this one didn't. What our research shows is that EBNA1 does actually impact on the p53 protein; it just does it in a different way than other viruses do."
Frappier, a Canada Research Chair in Molecular Virology, also conducted this research with Professor Aled Edwards, also of medical genetics and microbiology at U of T, and Professor Cheryl Arrowsmith, of medical biophysics at U of T and the Ontario Cancer Institute. Both Edwards and Arrowsmith are also from U of T's Banting and Best Department of Medical Research and the Structural Genomics Consortium.
The researchers tested the effects of EBNA1 on human cells grown in culture. Frappier says the paper provides a structural explanation of this protein complex so scientists can see in molecular detail how the EBNA1 protein binds to USP7 and the resulting impact on cell growth. Once that level of detail is achieved, she says scientists can then design specific mutations in these proteins to see what happens to cells when the proteins don't interact with one another. A better understanding of these molecular mechanisms will hopefully lead scientists and researchers to developing better methods of combating viruses like these which cause disease, says Frappier.
Funding for the study was provided by the Canadian Cancer Society through the National Cancer Institute of Canada and the Natural Sciences and Engineering Research Council of Canada.