Researchers at the Salk Institute have identified a key protein that allows herpes simplex virus (HSV) DNA to fly under the radar of their hosts' involuntary hospitality. Their findings may suggest a common mechanism by which viruses can successfully infect host cells.
To the host cell, invading viral DNA looks just like the product of DNA damage, which must be repaired or removed in order for the cell to stay healthy. As a result, DNA "security guards" continuously patrol our cells.
Matthew Weitzman, associate professor in the Laboratory of Genetics and the study's leader, and his team looked at what happens in a virusinfected cell when its DNA is damaged. In a normal cell, DNA damage sensor proteins rush to the site of damage. In cells infected with HSV, however, the cells' emergency repair teams don't respond correctly.
The team went on to identify a single viral protein that is to blame for knocking out the cell's security system, a protein called ICP0. They discovered that it flags for destruction two important DNA "security guards," the proteins called RNF8 and RNF168, thereby taking out the DNA damage response in human cells. ICP0 attaches so-called ubiquitin marks, which instruct the cell to get rid of the very proteins that protect it.
Delving deeper, the team looked at the role of these DNA "security guards" that are singled out by ICP0. Surprisingly, RNF8 and RNF168 also leave ubiquitin tags, but in this case, they mark regions of damage. They tag a protein called histone H2A, which directs DNA damage response proteins to accumulate at the sites of damage. The Salk team discovered that by removing RNF8 and RNF168, the viral ICP0 protein results in a decrease to the tag on the cellular H2A protein.
"We found that HSV targets the mark that is required to keep DNA damage sensors at damage sites," says postdoctoral researcher and first author Caroline Lilley. "We now think that HSV deliberately removes this mark so that the virus can infect cells without any trouble from its new host."
The findings highlight the importance of these histone marks in DNA damage. "By identifying how HSV dismantles the host's defense systems, we are shown the key steps, not only in viral infections, but also in the human DNA damage response," Weitzman explains.