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Development of a cellular reporter assay to measure activity of MutSβ, a therapeutic target for Huntington's disease

An, J.; Towle, T.; Aksit, M. A.; Mohiuddin, M.; Castaneda, S.; Nakashima, R.; Moccia, R.; Bulawa, C.; Fleming, J.

2023-09-09 neuroscience
10.1101/2023.09.07.555786 bioRxiv
Show abstract

Genetic modifiers of age of onset in Huntingtons disease (HD) provide compelling evidence that somatic expansion of the CAG repeats is a critical driver of pathogenesis and demonstrate that repeat instability is modulated by DNA mismatch repair (MMR). A component of this pathway, MutS{beta}, a heterodimer comprised of MSH2 and MSH3, has emerged as a potential target for small-molecule therapeutic intervention. However, a robust cellular assay to interrogate genetic and pharmacological modifiers of MutS{beta} has not been reported. We have repurposed and optimized a tetranucleotide reporter assay to measure MutS{beta} activity in MMR-competent cells. We show that repeat instability is modulated by MSH3 protein levels and by its ATPase activity. In addition, we show that an inhibitor of HDAC3 modulates repeat instability, demonstrating the utility of the assay for pharmacological studies.

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