Mayo Clinic research collaboration discovers why some DNA repair fails

Significant for Huntington’s disease and colon cancer

Mayo Clinic researchers have discovered the inner workings of a defective DNA repair process and are first to explain why certain mutations are not corrected in cells. The finding is important because genetic instability and accumulations of mutations lead to disease. This discovery may lead to ways of fixing the process to avoid Huntington’s disease and some types of colon cancer.

The Mayo team discovered that under certain conditions, a key protein fails to recognize a specific form of DNA that it needs to begin the repair process by recruiting additional proteins. They report their findings in a recent issue of Nature Structural and Molecular Biology. (http://www.nature.com/nsmb/journal/v12/n8/pdf/nsmb965.pdf). By failing to initiate repair, the defective mechanism may give rise to disabling inherited brain diseases such as Huntington’s disease, which causes select brain nerve cells to waste away. Huntington’s affects 30,000 adults in the United States, and another 150,000 Americans may be at risk of inheriting it. Friedreich’s ataxia is another neurodegenerative disease that may one day have a treatment based in part on this finding, as could a form of heritable colon cancer (hereditary non-polyposis colon cancer).

“Hereditary neurodegenerative diseases such as Huntington’s disease have no cure and no effective therapy,” says Cynthia McMurray, Ph.D., Mayo Clinic molecular biologist and lead investigator of the study. “Since the mutation initiates coding for the defective, toxic protein, we feel that it is likely that a successful effort to stop the steps leading to mutation will likely stop the progression of disease.”

Significance of the Research

Identifying this repair defect is important to designing new therapies for Huntington’s and other diseases. A commentary accompanying the journal article (http://www.nature.com/nsmb/journal/v12/n8/pdf/nsmb0805-635.pdf) welcomes the clarity the Mayo work brings to the problem of DNA’s abnormal expansion within a cell, which appears to be the underlying condition that leads to the repair defect. The commentator notes that the finding helps provide “the first clues for understanding the expansion” phenomenon, and that the significance is that “expansion of simple, primarily triplet DNA repeats seems to be responsible for an ever-growing number of human hereditary disorders.”

Dr. McMurray says the next step is to better understand the mechanism that causes the problem. “Towards this goal, we are currently dissecting the molecular mechanism by which the aborted function of this repair enzyme attenuates its normal repair pathway,” she says. “This is crucial information for understanding how to design new drugs or other interventions that help patients.”

A Day in the Life of DNA

From bacteria to humans, cells have evolved sophisticated means of repairing DNA that gets damaged — by a variety of causes — ranging from environmental stresses to inherent copying errors. Repair is necessary to prevent accumulations of mutations that can cause disease. Repair is therefore a normal part of a day in the life of DNA. As cells grow and divide, mismatch repair pathways are responsible for identifying irregular growth patterns and repairing specific irregularities in DNA.

Wrong Place at the Wrong Time

Dr. McMurray’s group studied a specific mismatch repair protein Msh2-Msh3 and found a paradox: Instead of helping repair DNA damage, under certain conditions, Msh2-Msh3 was actually harming the cell. Msh2-Msh3 did this when it arrived at the wrong place at the wrong time and bound to a specific portion of DNA (CAG-hairpin). This accident of binding at the CAG-hairpin altered the biochemical activity of Msh2-Msh3. This change in biochemical activity, in turn, promoted DNA expansion — rather than repair — and changed the function of Msh2-Msh3 from friend of DNA to foe by allowing damaged DNA to go unrepaired. Without DNA repair, mutations accumulate that lead to disease.

Collaboration and Support

In addition to Dr. McMurray, the research team at Mayo Clinic includes Barbara Owen, Ph.D.; Maoyi Lai; and John Badger, II. Other team members included: Zungyoon Yang and Jeffrey Hayes, Ph.D., from the University of Rochester, Rochester, N.Y.; Maciez Gajek and Teresa Wilson, Ph.D., from the University of Maryland in Baltimore; Winfried Edelmann, Ph.D., Albert Einstein College, Bronx, N.Y.; and Raju Kucherlapati, Ph.D., Harvard Medical School. Their work was sponsored by grants from the National Institutes of Health.