DNA mismatch repair protein Msh6 (MSH6)

DNA mismatch repair protein Msh6 (MSH6) is a key enzyme in the DNA mismatch repair (MMR) pathway, where it forms a heterodimer with MSH2 (MutSα complex) to recognize and initiate the repair of single base mismatches and small insertion-deletion loops generated during DNA replication[1][2][3]. MSH6 contains several conserved domains, an N-terminal disordered region, and nuclear localization signals, and acts as the DNA lesion-binding partner of MSH2[3]. Its activity is regulated by ATP binding and hydrolysis, which produce conformational changes necessary for repair signaling. Mutations or loss of MSH6 function lead to microsatellite instability, elevate mutation rates, and predispose to various cancers, including Lynch syndrome–associated colorectal and endometrial cancers[1][2][3][5]. MSH6 status is clinically significant both as a biomarker for immunotherapy response and risk stratification for hereditary cancer syndromes[1][2][3][5].

Other names

GTBPhMSH6GTMBPp160MSH-6G/T mismatch-binding proteinMutS protein homolog 6MutS-alpha 160 kDa subunitHNPCC5HSAPLYNCH5MMRCS3sperm-associated proteinmutS-like protein 6

Loss or mutation of MSH6 leads to DNA mismatch repair deficiency, causing microsatellite instability and increased mutation rates in tumor cells[1][2][3]. In oncology, MSH6 deficiency is a predictive biomarker for the efficacy of immune checkpoint blockade therapy, where tumors with high microsatellite instability (caused by defective MMR including loss of MSH6) display higher neoantigen loads and increased immunogenicity[2][3].