MutS beta complex (MutSβ) (MutSβ)

The MutS beta (MutSβ) complex is a heterodimeric protein assembly consisting of MSH2 and MSH3, which plays a vital role in the eukaryotic DNA mismatch repair (MMR) system (UniProt Consortium, 2023). It specifically recognizes and binds to larger insertion-deletion loops (IDLs) of up to 13 nucleotides, as well as certain base-base mismatches (Iyer et al., 2006). While its canonical function is to maintain genomic stability, MutSβ has been paradoxically implicated in the pathogenesis of trinucleotide repeat expansion disorders, such as Huntington's disease and Myotonic Dystrophy (Flower et al., 2019). In these diseases, the complex binds to CAG/CTG repeat hairpins and promotes somatic expansion, which correlates with earlier disease onset and increased severity (Tabrizi et al., 2020). Because MSH3 is the limiting subunit of the complex and is not essential for all MMR functions, it has emerged as a promising therapeutic target for slowing repeat expansion (Williams et al., 2020). Current drug development efforts focus on using antisense oligonucleotides (ASOs) or small molecules to reduce MSH3 expression or inhibit MutSβ activity (Triplet Therapeutics, 2021). However, a significant therapeutic challenge involves ensuring that the inhibition of MutSβ does not lead to microsatellite instability or an increased risk of cancer due to impaired DNA repair (Schmidt & Pearson, 2016).

Other names

MSH2-MSH3 complexhMutSβMutS-betaDNA mismatch repair protein MutS beta

Inhibition of MutSβ-mediated recognition and stabilization of DNA loops to prevent somatic expansion of trinucleotide repeats.