Friedrich’s ataxia is one of the most common hereditary ataxias and its most common molecular cause is a massive expansion in the number of GAA triplet nucleotide repeats in intron 1 of the frataxin gene on chromosome 9. There is no cure for the condition which damages the nervous system and can cause heart disease. Until now, research has been hampered by the lack of an animal model in which the GAA triplet expansions could be replicated and studied. But in the July 10 issue of Molecular Cell, researchers report that they have created such a model in yeast. In doing so, the scientists were able to analyze GAA repeat expansions and then identify cellular proteins that thwarted normal replication and promoted the elongated sequence. "In essence, we believe that the replication machinery occasionally gets tangled within a repetitive run, adding extra repeats while trying to escape," said Dr. Sergei Mirkin, senior author of the study. “And the longer the repeat, the more likely the entanglement is. That is as if a car which entered a roundabout misses the right exit due the heavy traffic and has to make the whole extra circle before finally escaping.” Dr. Mirkin and his team carried out a genetic screen to identify yeast proteins affecting repeat expansions. They found that the proteins within the cell that are known to facilitate the smooth replication fork progression decreased repeat expansions. Meanwhile the proteins responsible for the fork deviations, such as template switching and reversal, increased repeat expansions. It is possible that study of the yeast model may illuminate molecular mechanisms underlying Friedrich’s ataxia and may point the way toward effective interventions.
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