Mismatch repair protein MSH3 (MSH3) (MSH3)

Mismatch repair protein MSH3 is a critical component of the DNA mismatch repair (MMR) pathway, where it heterodimerizes with MSH2 to form the MutSβ complex [1, 8]. This complex is specialized for the recognition and repair of large insertion-deletion loops (typically greater than three nucleotides) and DNA interstrand cross-links [1, 12]. While MSH3 traditionally functions as a tumor suppressor, its role has recently been redefined as a primary genetic driver and therapeutic target in neurodegenerative repeat expansion disorders, most notably Huntington's disease [4, 5]. In these diseases, MSH3 inadvertently promotes the somatic expansion of CAG repeats, and reducing its levels via antisense oligonucleotides (ASOs) or siRNAs has been shown to halt this expansion in preclinical models [4, 6]. Furthermore, MSH3 status is a significant biomarker in oncology, as its deficiency leads to elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and sensitizes cells to platinum-based chemotherapies and PARP inhibitors [12, 15]. Therapeutic development currently focuses on CNS-targeted MSH3 knockdown to delay the onset and progression of neurodegeneration while minimizing systemic risks of genomic instability [1, 5]. Experimental agents like TTX-3360 have been developed to target MSH3 mRNA, although clinical progress has faced challenges [8]. Overall, MSH3 represents a unique target where its inhibition is sought to prevent pathological DNA expansion rather than simply correcting a repair deficiency [1, 4].

Other names

MutS homolog 3DUC1Divergent upstream proteinDNA mismatch repair protein Msh3

Inhibition of MSH3 expression to prevent somatic expansion of trinucleotide repeats in neurodegenerative diseases [4, 6], and modulation of DNA repair pathways to enhance sensitivity to DNA-damaging agents in cancer [7, 12].