Mayo Clinic Collaboration Discovers Protein Amplifies DNA Injury Signals
News Jan 27, 2006
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.
"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."
In earlier work, the Mayo Clinic researchers determined that MDC1 is important to the repair process - but they didn't know its role.
"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.
As genome editing technologies advance toward clinical therapies, they are raising hopes of a completely new way to treat disease. However, challenges need to be addressed before potential treatments can be widely used in patients. To tackle these challenges, the National Institutes of Health has launched the Somatic Cell Genome Editing program, which has awarded multiple grants including more than $3.6 million to assess the safety of genome editing in human cells and tissues.