Apr. 1, 2002 PHILADELPHIA - Epstein-Barr virus (EBV) infects almost every person worldwide at some point in life. Once infection occurs, the virus usually survives in the host forever, lying dormant and causing no symptoms. Occasionally, however, this latent EBV reactivates and contributes to certain human cancers, among them Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease.
Now, in a finding that could potentially guide development of new therapeutics against EBV-associated cancers, a study from The Wistar Institute reveals the unexpected mechanism for how EBV survives inside its host for so long.
Once settled in the host cell nucleus, the EBV genome uses a system of cellular proteins similar to the proteins at the ends of human chromosomes called telomeres, the researchers discovered. In both the virus genome and the human chromosome, these proteins are key to preserving genome integrity and, therefore, survival. When the researchers inhibited the telomeric protein complexes associated with EBV, the latent virus genome became unstable and was eventually lost from the cell. A report on the research appears in the March issue of Molecular Cell, to be published March 29.
The finding was particularly surprising because the structure of the virus genome and the human genome is so different: the virus' genome is circular while human genome is linear.
"It turns out that it doesn't matter whether the proteins bind to the end of a linear chromosome or exist independently on a circular chromosome - the basic function is the same," says study senior author Paul M. Lieberman, Ph.D., an associate professor at The Wistar Institute. "Those telomeric proteins are telling the cell not to destroy the viral DNA, and biologically, that's very interesting."
In undertaking this research, Lieberman's research group wanted to find out what allows EBV to survive in the host cell nucleus as an independent genome for such a long time. They knew that when the virus replicated in the dormant stage, it maintained stable copies of its genome even as the cell divided, and in this way maintained itself in the daughter cells. They also knew that EBV survival required the presence of a viral protein called EBNA1 that binds to the viral site where DNA replication begins and signals the cellular machinery to replicate the viral genome at the precise moment that the cellular genome replicates.
They believed that EBNA1 didn't work alone, however. Rather, they believed that it worked with one or more cellular proteins to initiate viral DNA replication and ensure its maintenance. Using biochemical methods of DNA affinity purification coupled with mass spectroscopy, the group succeeded in identifying three proteins involved in the process: a protein called Telomeric Repeat Binding Factor 2 (TRF2); a TRF2-interacting protein known as hRap1; and telomere-associated poly-ADP ribose polymerase, or Tankyrase. Lieberman's group went on to show that these same telomere-binding proteins interact with EBNA1 and are required for the virus to maintain its DNA and survive during latency. Mutations to these proteins, experiments showed, led to the loss of the latent viral genome; the virus could no longer survive in the host cell.
In the process of identifying these proteins and their function, Lieberman's group discovered the virus' unanticipated, telomeric-like strategy for replication and maintenance.
In addition to the biological significance of the findings, there may be medical implications, as well, Lieberman notes.
"In malignancies where EBV is known to be a contributing agent, inactivating the mechanism by which the virus maintains its genome could inhibit tumor cell growth," Lieberman says. "Such a therapeutic approach might also be effective against EBV and other related members of the herpes virus family, although this remains to be shown."
In addition to senior author Lieberman, the remaining coauthors on the Molecular Cell study are Zhong Deng, Larissa Lezina, Chi-Ju Chen, Svetlana Shtivelband, and Wingkan So, all at The Wistar Institute. The research was supported by grants from the National Institutes of Health, the American Cancer Society, and the Leukemia/Lymphoma Society of America.
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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