The Mechanism of Large-Scale CAG Expansion.
Dinter, Teresa.
2016
- Nearly 30 genetic diseases are caused by the repetition of a short sequence of 2-9 base pairs, known as microsatellites. These microsatellite repeats occur in humans normally; however disease symptoms become apparent once a certain repeat threshold is reached. Usually, these diseases follow a phenomenon known as genetic anticipation, in which each subsequent generation experiences increased disease ... read moreseverity and earlier onset, which was found to correlate with microsatellite repeat length. To study these expansions, budding yeast (S. cerevisiae) strains have been designed to carry repeats within or near selectable genes. On selective media, cells with expansions will form colonies, allowing for their detection. Here, proteins were investigated by two approaches to determine their effect on large-scale CAG repeat expansion. First, a candidate gene approach was used to test two Holliday junction resolvases, Mus81 and Yen1, because homologous recombination had previously been shown to be involved in large-scale CAG repeat expansion. Second, in an unbiased genetic screen, Los1 had two independent hits as a gene protecting against CAG expansion. It was of particular interest because of its role at the nuclear pore in tRNA export and a recent study had found that expanded CAG repeats were repaired at the nuclear pore. To characterize the roles of these proteins, knockout strains were created and fluctuation assays were performed to calculate CAG expansion rates. The double mus81Δyen1Δ strain showed a decrease in the expansion rate, suggesting that these proteins are required for CAG expansion to occur. The Los1 results suggest that los1Δ increased canavanine resistance, but does not affect repeat expansion directly.read less
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