DNA mismatch repair protein Msh3 (MSH3)

DNA mismatch repair protein Msh3 (MSH3) is a critical enzyme in the DNA mismatch repair (MMR) pathway, functioning as a heterodimer with MSH2 to form the MutS beta complex [1, 4]. This complex is specifically responsible for identifying and initiating the repair of large insertion-deletion loops (IDLs) and certain mispaired bases, which is essential for maintaining the stability of the human genome [3, 5]. Beyond its protective role, MSH3 has been identified as a major driver of somatic repeat expansion in neurodegenerative conditions such as Huntington's disease, where it inadvertently promotes the lengthening of toxic CAG repeats [2, 8, 10]. In the context of oncology, mutations or loss of MSH3 expression are linked to microsatellite instability (MSI) and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), particularly in colorectal and endometrial cancers [6, 15, 17]. Therapeutic development focuses on inhibiting MSH3 using antisense oligonucleotides (ASOs) or siRNAs to slow disease progression in repeat expansion disorders [1, 8]. Current evidence suggests that targeted reduction of MSH3 in the central nervous system may be well-tolerated, offering a unique therapeutic window to treat neurodegeneration while avoiding systemic genomic instability [2, 10].

Other names

MutS homolog 3hMSH3Divergent upstream proteinMismatch repair protein 1DUPMRP1DUC1DUGFAP4

MSH3 is targeted primarily through gene silencing mechanisms, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), which reduce MSH3 mRNA and protein levels to prevent toxic DNA repeat expansion [1, 8, 10]. Additionally, experimental small molecules and cyclic peptides are being developed to inhibit the protein-protein interaction between MSH3 and MLH1 or MSH2, thereby disrupting the formation of the functional MutS beta complex [9].