All life forms on Earth, from prokaryotes to humans, have developed sophisticated DNA repair mechanisms that allows the cells to repair damage to the DNA molecule due to such events as environmental stress or errors during the replication of the genetic code. As cells undergo such processes as mitosis and meiosis, mismatch repair pathways identify and repair irregularities in DNA to prevent the accumulation of mutations, which could possibly result in disease. Recently, researchers from Mayo Clinic have uncovered a greater depth of knowledge regarding these repair pathways and are the first to explain why the correction of specific mutations sometimes does not occur in cells. The sufferers of neurodegenerative diseases such as Huntington’s disease and Friedrich’s Ataxia and even colon cancer may eventually have effective treatments stemming from this discovery. The researchers found that an important protein neglects to recognise a specific form of DNA that is essential in beginning the repair pathway by the recruitment of necessary additional proteins. It is believed that the diseases aforementioned are a result of the cells’ failure to initiate repair and the subsequent formation of toxic aggregates within cells, which inhibit homeostatic cellular functioning.
Cynthia McMurray, Ph.D. lead investigator of the study stated that ‘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 the disease.’ It was also found that under certain conditions, a specific mismatch repair protein, Msh2-Msh3, was found to damage the cell instead of assisting in repair of the DNA. This occurred when the protein arrived at an inopportune time and location and bound to a section of DNA which altered the homeostatic biochemical activity and thus promoted DNA expansion, as opposed to repair. This expansion is a key feature of diseases such as Huntington’s disease in which the IT15 gene, located on chromosome 4, undergoes a pathological expansion of an unstable CAG trinucleotide repeat within the coding region of the Huntingtin (htt) gene. The normal range of 6-35 is resultantly expanded to 36-121 and disrupts essential cellular processes such as energy metabolism, gene transcription, intraneuronal trafficking, post-synpatic signalling, clathirn-dependent endocytosis and the workings of the ubiquitin-proteasome system. Mitochondrial function and CNS energy metabolism also seem to be affected when the disease comes to fruition. The combined effects therefore result in the loss of neurons and selective neural dysfunction in the striatum, cerebral cortex and other areas of the brain.
The research is now being used to further understand the mechanisms which causes these problems. Dr.McMurray stated, ‘Towards this goal, we are currently dissecting the molecular mechanism by which the aborted function of this repair enzyme attenuates its normal repair pathway. This is crucial information for understanding how to design new drugs or other interventions to help patients.’ If such advances could be made, the longevity of those suffering these diseases could be vastly improved. Currently Huntington’s Disease is a neurodegenerative disorder which is typically fatal within 15-20 years of diagnosis and the condition cannot be stopped, slowed or reversed.
Nick Ravenswood (42005470)
Link to original article -
http://www.sciencedaily.com/releases/2005/10/051010100302.htm
