Engineered Virus Could Lead to Effective Cancer Treatment

Researchers examine how a cell distinguishes between damaged DNA and foreign viral DNA.

Researchers examine how a cell distinguishes between damaged DNA and foreign viral DNA.

Organisms must protect their DNA at all costs, whether that means protecting against damaged DNA or against foreign DNA of an invading virus. But how the body tells the difference between the two has been a mystery to scientists up until now.

Scientists at the Salk Institute have recently discovered the details of how a cell’s response system distinguishes between damaged DNA and foreign viral DNA. The discovery could help in the development of new cancer-selective viral therapies and may additionally explain why aging and certain diseases are more susceptible to viral infections.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, associate professor and senior author of the study, which was published in Cell on August 27, 2015. “The findings may also explain why certain conditions like aging, cancer chemotherapy and inflammation make us more susceptible to viral infection.”

Breaks in our DNA can be caused by many factors including radiation. Researchers detailed how a cluster of proteins called the MRN complex detects both DNA and viral breaks and amplifies its response through histones, packaging proteins that wrap genetic material into small bundles like Styrofoam peanuts. MRN activates histones on surrounding chromosomes and then that calls forth a plethora of additional proteins, resulting in a cell-wide, high-alert alarm to help mend the DNA.

When a cell can’t mend the DNA break, it will self-destruct, killing the chance of reproduction and thus tumor growth.

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

Findings from the Salk study revealed that a cell’s response system begins the same way (with MRN detecting either DNA or viral breaks) but never sends out the global alarm signal in the case of the virus.

Commonly, a DNA virus will enter the cell nucleus and turn on genes to replicate its own DNA. Without signaling the entire body to arrest and kill the cell, the cell detects the replication of unwanted DNA and the MRN complex grabs and selectively neutralizes the virus.

In this way, the MRN response stays localized so as not to kill the cell, and prevents viral, but not cellular, replication. If every incoming virus spurred a similarly strong response our cells would be frequently paused, hampering our growth, according to O’Shea.

When both threats are posed to the body simultaneously, the MRN will activate the massive response at the DNA break, but no MRN is left to respond to the virus. This means that the virus will continue to travel throughout the body undetected as the MRN attend to the more massive signal.

“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” 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 might explain the reason why people with conditions such as cancer and inflammation result in high levels of cellular DNA damage and make patients 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 Govind Shah, first author and a former research associate at the Salk Institute. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

The next step for scientists is to engineer a virus specifically targeted to sneak by the MRN complex and replicate specifically in cancer cells. In cancer cells, MRN is already so preoccupied with responding to DNA breaks in cancer cells that an engineered virus could potentially get through undetected.

“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,” O’Shea said.

As scientists work to figure out the specifics of this next endeavor, mankind gets one step closer to finding an alternative treatment to combat cancer. The viral approach could lead to a way for scientists to effectively kill cancer without posing threats to the body with radiation.