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Herpes virus hijacks DNA repair process

June 13, 2007 -- Scientists probing the details of viral infection have discovered an intriguing surprise: in mice, herpes viruses hijack their host cells' tools for fixing DNA damage and use those tools to enhance their own reproduction.

The DNA damage response normally fixes DNA errors caused by radiation or other environmental factors, or mistakes accidentally introduced when cells copy their genetic material prior to dividing.

In the murine (or mouse-infecting) herpes virus they studied, researchers at Washington University School of Medicine in St. Louis identified a protein that can trick the mouse cell into turning on the DNA damage response. They also showed that Epstein-Barr virus, a human herpes virus, has a similar protein. Scientists found that blocking murine herpes virus from activating the DNA damage response caused viral replication rates to plummet.

"We don't want to treat viral infection by blocking DNA damage response systemically because this process is used constantly throughout the body and is very important to preventing cancer," says lead author Vera Tarakanova, Ph.D., a postdoctoral fellow. "However, by targeting the viral protein responsible for activating the DNA damage response, we may be able to block viral replication. In addition, determining how the DNA repair response helps viral replication may enable us to develop novel strategies to treat infection."

The paper appears online this week in Cell Host & Microbe. Scientists have known for some time that viral infection of cells activates the DNA damage response. But researchers had assumed that this activation occurred because repair mechanisms were mistaking replicating viral DNA for damaged or dysfunctional cellular DNA.

"Viruses sometimes structure their own DNA differently than cellular DNA," Tarakanova notes. "Many of us thought that such differences might be triggering the DNA damage response." Working in the laboratory of H erbert W. "Skip" Virgin, M.D., Ph.D., Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology, Tarakanova found that murine herpes virus, rather than the host cell, was triggering the DNA damage response. She showed that introducing just one viral protein into cells led to activation of two cellular proteins involved in the damage response, ATM and H2AX.

The viral protein that triggered this inappropriate activation, orf36, is a kinase, a type of protein that chemically modifies other molecules to activate different processes or transmit signals. Genetic comparisons with several human herpes viruses revealed kinases similar to orf36 in the human viruses. Scientists then took a similar kinase from human Epstein-Barr virus and showed that introducing it into cells also activated the DNA damage response.

When the research team genetically disabled orf36 in the murine herpes virus and infected mouse cells with it, the virus no longer activated the DNA damage response. The virus's ability to replicate also dramatically decreased.

Kinases are versatile proteins that sometimes play multiple roles. To ensure that enhanced viral replication wasn't linked to orf36's interactions with other molecules, researchers turned to mice lacking the genes for ATM and H2AX, the damage response proteins activated by infection. When they infected cells from these mice with murine herpes virus, its ability to reproduce was again curtailed. How DNA damage response benefits viral replication is still a mystery and a topic of continuing investigation in the Virgin lab.

"The discovery that induction of the cells' DNA damage response is an intentional viral strategy, rather than a passive cellular response to viral invasion, means that we should look into whether other DNA viruses use a similar approach to enhance their growth," says Virgin.


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Source:Washington University School of Medicine


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