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Researchers show how cells' DNA repair machinery can destroy viruses
Date:1/21/2013

s, "They're not replicating their DNA and dividing, so they couldn't care less if they have a lot of dUTP."

This is a critical piece of information, Stivers says, because when a retrovirus like HIV invades a cell, its first order of business is to make a DNA copy of its own genome, then insert that copy into the host cell's genome. If there are many dUTPs floating around in the cell, they will likely make their way into the new viral DNA, and, potentially, later be snipped out by hUNG2. The question, Stivers says, left open by the conflicting results of previous studies, was what effect, if any, this process has on HIV and other viruses.

To address this question, Amy Weil, a graduate student in Stivers' laboratory, measured dUTP levels and hUNG2 activity in a variety of human cells grown in the laboratory, then exposed them to HIV. Cells with high dUTP but little hUNG2 activity succumbed easily to the virus, which appeared to function just fine with a U-ridden genome. Similarly, cells with low dUTP levels but high hUNG2 activity were susceptible to HIV. For these cells, it seemed, hUNG2 would snip out the few stray Us, but the resulting holes would be repaired, leaving the viral DNA as good as new.

But in cells with both high dUTP and vigilant hUNG2, the repair process turned into a hack job, Stivers says, leaving the viral DNA so riddled with holes that it was beyond repair. "It's like dropping a nuclear bomb on the viral genome," he says.

By showing how dUTP and hUNG2 work together to protect resting cells from infection, Stivers says, the study identifies a new pathway that could restrict HIV infection in non-dividing cells. Current anti-retroviral drugs effectively suppress the virus, but, Stivers explains, they miss copies of the virus that hide out in non-dividing cells, and "the minute you stop taking anti-retrovirals, it starts replicating again." He suggests that drug strategies could be devised to target this pathway in
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Contact: Shawna Williams
shawna@jhmi.edu
410-955-8236
Johns Hopkins Medicine
Source:Eurekalert  

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