Salk Scientists Find Evidence For "Hit and Run" Cancer Mechanism
La Jolla, CA – A team led by Salk Institute scientists may have discovered how viruses can "hit and run" a cell's genetic machinery to trigger cancer and exit without a trace.
The Salk team showed that a common respiratory virus, called adenovirus, can disrupt a cellular sensor that detects damage to DNA. Disabling this sensor can render ineffective key growth-controlling genes, resulting in mutations that lead to cancer.
"Specifically, the virus disables proteins within a complex that is involved in detection and repair of chromosomal breaks, the type of damage caused by X-rays," said Matthew Weitzman, assistant professor of genetics at the Salk and senior author of the study appearing in today's Nature.
"This is the first demonstration of a virus interacting with this critical machinery. It does so to further its own ends – to make copies of itself and continue infection – but the unfortunate side effect is to compromise a cell's genetic material."
Weitzman and his colleagues showed that when adenovirus infects human cells grown in culture, several of its proteins can target a complex called M/R/N (for Mre11, Rad50 and NBS1/nibrin/p95). The job of the M/R/N complex is to detect breaks in DNA strands. It then instructs specialized DNA repair machinery to set about knitting the breaks together.
Adenovirus is one of a class of viruses called double-stranded DNA viruses. When these viruses infect a cell, they make thousands of copies of its genetic material – small linear fragments of DNA that resemble broken chromosomes. These fragments are then packaged inside viral protein shells and released to initiate new infections.
"It seemed likely that if adenovirus did not disable the damage sensor, the cell's machinery would start stitching together the individual viral genomes into long concatemers that could not be packaged," said Weitzman.
His team showed that this was in fact the case by disabling the viral proteins that disrupt M/R/N. They found long strands of strung-together viral genomes, which seriously compromised infection.
"Therefore, it appears that the virus evolved its ability to disrupt DNA damage machinery to aid its own survival," said Weitzman.
Although adenoviruses have not been associated with any human cancers yet, they do transform rodent cells in culture, and the proteins Weitzman's group showed to disrupt DNA repair have been implicated in the "hit and run" process.
"It may be that adenoviruses are triggering cancers, but the infections are cleared long before cancer is diagnosed," said Weitzman. "We may need to develop new ways of looking for evidence of the virus."
First author Travis Stracker and second author Christian Carson are graduate students at the University of California, San Diego conducting thesis research in Weitzman's laboratory. The study, titled "Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex," was funded by the National Institutes of Health, the Joe W. and Dorothy Dorsett Brown Foundation, the James B. Pendleton Foundation, and the Lebensfeld Foundation. Stracker is supported by an NIH training grant to UCSD and by fellowships from the Chapman Foundation, the Legler Benbough Foundation and the Salk Institute Association.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.