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Depletion of MutSbeta slows GAA•TTC repeat expansion in a cellular model of Friedreich Ataxia

Friedreich Ataxia (FRDA) is caused by expansion of a GAA•TTC triplet repeat in the first intron of the frataxin gene. FRDA is a fatal, autosomal recessive disease characterized by rapidly progressing neurodegeneration. Disease severity directly correlates with GAA•TTC repeat number. We have developed a human cellular model of FRDA that recapitulates the incremental, continuous expansion found in post‐mitotic tissues of affected patients. Our hypothesis is that repeat expansion is mediated by DNA repair enzymes in the mismatch repair pathway that are attracted to unusual structures formed by transcription through the GAA•TTC repeat. DNA mismatches and small loop‐outs are recognized by MutS heterodimers MutSalpha or MutSbeta (composed of MutS Homologue 2 (MSH2) and MSH6 or MSH2 and MSH3, respectively). We found that shRNA depletion of MSH2 or MSH3, but not MSH6, slowed GAA•TTC expansion in our FRDA model. We conclude that although MSH2 depletion is associated with colorectal cancer, targeting MSH3 has promising therapeutic potential in slowing FRDA progression. Funded by grants from the Friedreich's Ataxia Research Alliance and the LSUHSC Research Enhancement Fund.