MSH3 (mutS homolog 3) is a DNA mismatch repair (MMR) protein that forms the MutSβ complex with MSH2, recognizing and binding to large insertion-deletion loops and DNA mismatches to initiate repair processes 1. In disease contexts, MSH3 plays a critical role in somatic CAG repeat expansion, particularly in neurodegenerative disorders like Huntington's disease (HD). MSH3 drives the expansion of CAG repeats in striatal medium spiny neurons and other vulnerable cell types, with expansion rates reaching 8.8 repeats per month in HD mouse models 2. This somatic expansion accelerates disease onset and progression in HD 3. Therapeutically, MSH3 represents an attractive target because it is relatively tolerant of loss-of-function variation in humans, unlike other MMR genes 3. Antisense oligonucleotides and siRNA targeting MSH3 effectively reduce somatic CAG expansion in HD models without causing cancer-associated microsatellite instability 34. Germline biallelic MSH3 mutations cause a recessive form of colorectal adenomatous polyposis, demonstrating its importance in tumor suppression 5. MSH3 levels are upregulated in HD and spinocerebellar ataxia patient brains, where it works with MSH2 to promote pathogenic repeat expansions 67.