DNA mismatch repair protein Msh3 (MSH3) (MSH3)

DNA mismatch repair protein Msh3 (MSH3) is a critical component of the MutS beta (MutSβ) heterodimer, which also includes MSH2. This complex is specialized in recognizing and initiating the repair of larger DNA insertion-deletion loops, typically those greater than two nucleotides in length [1]. While essential for maintaining genomic stability, MSH3 has been identified as a primary driver of somatic CAG repeat expansion in Huntington's disease and other repeat expansion disorders [2, 3]. Genetic studies have shown that higher levels or specific variants of MSH3 correlate with earlier disease onset and faster progression by promoting the continued lengthening of toxic repeat sequences in neurons [3, 5]. Consequently, MSH3 is being pursued as a therapeutic target, with drug candidates like SKY-0515 and TTX-3355 designed to lower MSH3 levels via RNA-targeted mechanisms [4]. The goal of these therapies is to stabilize repeat lengths and preserve neuronal function, thereby slowing or halting disease progression. However, therapeutic intervention must balance the benefit of repeat stabilization against the potential risk of increased mutation rates in other genomic regions, such as Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST), which could theoretically increase cancer risk [5].

Other names

MutS homolog 3Mismatch repair protein 1MRP1MutS-beta 92 kDa subunitDUP

Reduction of MSH3 protein levels via antisense oligonucleotide (ASO) mediated mRNA degradation or small molecule-induced modulation of RNA splicing to inhibit somatic expansion of CAG repeats [4, 5].