Damage response to viral attack points to possible cancer treatment

By John Murphy, MDLinx
Published January 13, 2016

Key Takeaways

Why do viral infections seem more common in the elderly or in people with disease? A new discovery that identifies how a cell distinguishes damage between its own DNA and the DNA of an invading virus may have the answer.

The research, published online August 27, 2015 in Cell, even suggests a method to exploit this viral identification through the development of viral-based therapies that specifically target cancer cells.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said the study’s senior author Clodagh O’Shea, PhD, Associate Professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies, in La Jolla, CA. “The findings may also explain why certain conditions like aging, cancer, chemotherapy, and inflammation make us more susceptible to viral infection.”

Many factors, such as chemoradiation, can cause a break in a cell’s DNA. The researchers identified how a cluster of proteins—the MRN complex—detects both DNA and viral breaks. However, MRN incites a distinctly different response to cellular DNA damage than it does to DNA viruses.

For cellular DNA damage, MRN puts out a distress call on a global scale—a cell-wide, all-hands-on-deck alarm to help mend the DNA by summoning additional proteins from surrounding chromosomes.

“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr. O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”

But for viral DNA breaks, MRN simply implements a localized response that specifically prevents viral, but not cellular, DNA replication. The localized response is necessary, Dr. O’Shea noted, because if every incoming virus spurred a wide-scale global response, our cells would be paused repeatedly, hampering growth.

When both threats to the genome occur at the same time, something’s gotta give—so MRN activates the massive response at the DNA break, with nothing left to respond to the virus. “The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr. O’Shea said. “When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”

This may explain why people with conditions resulting in high levels of cellular DNA damage—such as cancer, chemotherapy, inflammation, and aging—are more susceptible to viral infections.

“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” said first author Govind Shah, PhD, a research associate at the Salk Institute. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

Cancer cells, unlike normal cells, intrinsically have very high levels of DNA damage. So, the MRN in cancer cells is already so preoccupied with responding to DNA breaks that a virus can sneak in undetected. Dr. O’Shea’s lab plans to use this new discovery to create novel engineered viruses that would be destroyed by normal cells but will replicate specifically in cancer cells.

“Cancer cells by definition have high mutation rates and genomic instability even at the very earliest stages, so you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic,” Dr. O’Shea explained.

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