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Discovery Of Why Some DNA Repair Fails: Significant For Huntington's Disease And Colon Cancer

Date:
October 10, 2005
Source:
Mayo Clinic
Summary:
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.

ROCHESTER, Minn. -- Mayo Clinic researchers have discovered the innerworkings of a defective DNA repair process and are first to explain whycertain mutations are not corrected in cells. The finding is importantbecause genetic instability and accumulations of mutations lead todisease. This discovery may lead to ways of fixing the process to avoidHuntington's disease and some types of colon cancer.

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The Mayo team discovered that under certain conditions, a keyprotein fails to recognize a specific form of DNA that it needs tobegin the repair process by recruiting additional proteins. They reporttheir findings in a recent issue of Nature Structural and MolecularBiology. (http://www.nature.com/nsmb/journal/v12/n8/pdf/nsmb965.pdf).By failing to initiate repair, the defective mechanism may give rise todisabling inherited brain diseases such as Huntington's disease, whichcauses select brain nerve cells to waste away. Huntington's affects30,000 adults in the United States, and another 150,000 Americans maybe at risk of inheriting it. Friedreich's ataxia is anotherneurodegenerative disease that may one day have a treatment based inpart on this finding, as could a form of heritable colon cancer(hereditary non-polyposis colon cancer).

"Hereditary neurodegenerative diseases such as Huntington'sdisease have no cure and no effective therapy," says Cynthia McMurray,Ph.D., Mayo Clinic molecular biologist and lead investigator of thestudy. "Since the mutation initiates coding for the defective, toxicprotein, we feel that it is likely that a successful effort to stop thesteps leading to mutation will likely stop the progression of disease."

Significance of the Research

Identifying this repair defect is important to designing newtherapies for Huntington's and other diseases. A commentaryaccompanying 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'sabnormal expansion within a cell, which appears to be the underlyingcondition that leads to the repair defect. The commentator notes thatthe finding helps provide "the first clues for understanding theexpansion" phenomenon, and that the significance is that "expansion ofsimple, primarily triplet DNA repeats seems to be responsible for anever-growing number of human hereditary disorders."

Dr. McMurray says the next step is to better understand themechanism that causes the problem. "Towards this goal, we are currentlydissecting the molecular mechanism by which the aborted function ofthis repair enzyme attenuates its normal repair pathway," she says."This is crucial information for understanding how to design new drugsor other interventions that help patients."

A Day in the Life of DNA

From bacteria to humans, cells have evolved sophisticated means ofrepairing DNA that gets damaged -- by a variety of causes -- rangingfrom environmental stresses to inherent copying errors. Repair isnecessary to prevent accumulations of mutations that can cause disease.Repair is therefore a normal part of a day in the life of DNA. As cellsgrow and divide, mismatch repair pathways are responsible foridentifying irregular growth patterns and repairing specificirregularities in DNA.

Wrong Place at the Wrong Time

Dr. McMurray's group studied a specific mismatch repair proteinMsh2-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 timeand bound to a specific portion of DNA (CAG-hairpin). This accident ofbinding at the CAG-hairpin altered the biochemical activity ofMsh2-Msh3. This change in biochemical activity, in turn, promoted DNAexpansion -- rather than repair -- and changed the function ofMsh2-Msh3 from friend of DNA to foe by allowing damaged DNA to gounrepaired. Without DNA repair, mutations accumulate that lead todisease.

Collaboration and Support

In addition to Dr. McMurray, the research team at Mayo Clinicincludes Barbara Owen, Ph.D.; Maoyi Lai; and John Badger, II. Otherteam members included: Zungyoon Yang and Jeffrey Hayes, Ph.D., from theUniversity of Rochester, Rochester, N.Y.; Maciez Gajek and TeresaWilson, Ph.D., from the University of Maryland in Baltimore; WinfriedEdelmann, Ph.D., Albert Einstein College, Bronx, N.Y.; and RajuKucherlapati, Ph.D., Harvard Medical School. Their work was sponsoredby grants from the National Institutes of Health.



Story Source:

The above story is based on materials provided by Mayo Clinic. Note: Materials may be edited for content and length.


Cite This Page:

Mayo Clinic. "Discovery Of Why Some DNA Repair Fails: Significant For Huntington's Disease And Colon Cancer." ScienceDaily. ScienceDaily, 10 October 2005. <www.sciencedaily.com/releases/2005/10/051010100302.htm>.
Mayo Clinic. (2005, October 10). Discovery Of Why Some DNA Repair Fails: Significant For Huntington's Disease And Colon Cancer. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/2005/10/051010100302.htm
Mayo Clinic. "Discovery Of Why Some DNA Repair Fails: Significant For Huntington's Disease And Colon Cancer." ScienceDaily. www.sciencedaily.com/releases/2005/10/051010100302.htm (accessed November 28, 2014).

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