Human MutS alpha mismatch repair complex (hMutSα) (hMutSα)

The Human MutS alpha (hMutSα) mismatch repair complex is a protein heterodimer consisting of MSH2 and MSH6 that serves as a primary sensor for DNA replication errors (UniProt P43246, P52701). It specifically recognizes base-base mismatches and small insertion-deletion loops, initiating the DNA mismatch repair (MMR) pathway to maintain genomic stability (Kunkel and Erie, 2005, PMID: 16038671). In a pharmacological context, hMutSα is the critical mediator of the cytotoxicity of thiopurine drugs, such as 6-thioguanine, and alkylating agents like temozolomide. These drugs result in the formation of 6-methylthioguanine (6-MeTG) or O6-methylguanine (O6-MeG) in DNA, which pair with thymine; hMutSα recognizes these mismatches and triggers a "futile repair cycle" or direct apoptotic signaling (Karran and Attard, 2008, PMID: 18311171). Deficiency in this complex, often seen in Lynch syndrome or sporadic cancers with microsatellite instability, leads to high mutation rates and profound resistance to these chemotherapeutic agents (Li, 2008, PMID: 18246114). Thus, hMutSα is both a guardian of the genome and a necessary component for the efficacy of specific DNA-damaging therapies. Its role in drug response makes it a significant factor in personalized oncology and the study of drug resistance mechanisms.

Other names

MSH2-MSH6 heterodimerMutS alphaHuman MutS homolog alphahMutS alphaDNA mismatch repair protein MSH2-MSH6 complex

The complex recognizes DNA lesions such as 6-methylthioguanine:thymine or O6-methylguanine:thymine mismatches, which triggers a futile repair cycle or direct signaling to the cell cycle machinery (e.g., ATR/CHK1), ultimately leading to G2/M arrest and apoptosis (PMID: 10523315, 18311171).