MutS homolog 3 (MSH3) (MSH3)

MutS homolog 3 (MSH3) is a key component of the post-replicative DNA mismatch repair (MMR) system, where it heterodimerizes with MSH2 to form the MutS beta complex [4, 11]. This complex is specialized for the recognition and repair of large insertion-deletion loops and tetranucleotide repeat mismatches, playing a vital role in maintaining genomic stability [6, 11]. Beyond its canonical tumor-suppressive role, MSH3 has been identified as a primary genetic driver of somatic expansion in trinucleotide repeat disorders such as Huntington's disease and Myotonic Dystrophy [1, 7]. In these conditions, MSH3 inadvertently promotes the progressive lengthening of toxic CAG or CTG repeats in neurons, which accelerates disease onset and clinical progression [2, 8]. Therapeutic strategies currently under development include antisense oligonucleotides (ASOs) and siRNA designed to lower MSH3 levels in the central nervous system to slow or halt this expansion [3, 14]. While MSH3 deficiency is associated with the 'elevated microsatellite alterations at selected tetranucleotide repeats' (EMAST) phenotype in various cancers, human genetic data suggests that partial loss of MSH3 function is relatively well-tolerated, offering a promising therapeutic window for neurodegenerative intervention [4, 7].

Other names

Mismatch repair protein 1MRP1Divergent upstream proteinDUPFAP4HMSH3MutS (E. coli) homolog 3

Reduction of MSH3 protein levels via antisense-mediated mRNA degradation or RNA interference to halt somatic repeat expansion; small molecule inhibition of the MutS beta complex to prevent DNA loop recognition.