A Mayo Clinic-led research collaboration has discovered that the protein MDC1 amplifies weak DNA injury signals so genetic repair can begin.
Once amplified, even low-level damage signals become strong enough to activate the cell's natural repair processes while the injury is most tractable to repair.
How this "distress call" was communicated wasn't clear until this finding, which appears in the January 20 issue of Molecular Cell. The research was conducted in collaboration with colleagues from Harvard University and the University of Texas, Austin.
"It's important that DNA lesions get repaired because then we don't get mutations," says Junjie Chen, Ph.D., Mayo Clinic oncology researcher and leader of the Mayo Clinic team. "This is just one mechanism involved in communicating injury to the repair processes, but it's an important start to understanding how we might one day design new treatments that help this repair system recover from injury or resist injury."
Dysfunction of the DNA damage response pathway makes the gene unstable. Genomic instability is the driving force in tumor formation, which is why cancer researchers around the world are focusing on understanding the DNA damage response pathway. Knowing how the cell communicates DNA injury to alert the repair system is an important first step to designing new therapies for cancers and other diseases.
The damage control process is continual and essential to health. DNA must repair itself so the instructions it gives to operate bodily functions are correct. In earlier work, the Mayo Clinic researchers determined that MDC1 is important to the repair process -- but they didn't know its role.
DNA is easily and often damaged by environmental and chemical sources such as ultraviolet radiation, cigarette smoke, and other natural and artificial toxins. These create injury sites or lesions. In healthy situations, DNA repair signal pathways are competently monitoring for damage and alerting the repair system when DNA lesions are detected.
"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.
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.
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 of Texas, Austin, include Tanya Paull, Ph.D. and Melissa Rivera. Collaborators from the National Cancer Institute were Andre Nussenzweig, Ph.D. and Arkady Celeste, Ph.D. The work was supported by grants from the National Institutes of Health.