"Most of the time we don't really encounter severe damage in the cell; most of the damage to DNA is mild injury -- such as low doses of sunlight," notes Dr. Chen. "But it's still injury, and we want to repair it as soon as possible so things don't get worse. That's why our question was: How does the cell detect low-dose damage signals? We believe this amplification process involving MDC1 is the answer to that question, and that it is critical because it's involved in even very subtle injury, such as a single DNA strand break -- which is very small. It is a very sensitive communication pathway."
To investigate the role of the protein MDC1, the researchers disrupted the MDC1 gene in mice and compared them to normal mice. The engineered strain of mice lacking MDC1 was extremely sensitive to DNA damage -- and unable to repair it. The MDC1-deficient mice showed symptoms of growth retardation, male infertility, immune defects and chromosome instability.
The Next Step
Now that they understand MDC1's role in amplifying distress calls from injured DNA to cue the repair process, the Mayo researchers are investigating another system that appears to play a similar role in the cell. "If we can understand all the pathways involved in signaling the DNA repair process, we may be able to develop a comprehensive approach to managing the signals to treat disease," says Dr. Chen.
Collaboration and Support
Other members of the Mayo Clinic research team include: Zhenkun Lou, Ph.D.; Katherine Minter-Dykhouse; and Jan van Deursen, Ph.D. Team members from Harvard Medical School include Sonia Franco, M.D., Ph.D.; Monica Gostissa, Ph.D.; John Manis, M.D.; and Frederick Alt, Ph.D. Team members from the University