| MSH6 is a MutS family DNA mismatch repair protein that forms the MutSα heterodimer with MSH2 and functions as a primary sensor of base–base mismatches and short insertion–deletion loops in post-replicative chromosomal DNA, linking mismatch recognition to repair and broader DNA damage responses. The protein carries an N‑terminal disordered region containing the PWWP chromatin-binding domain and multiple regulatory motifs, a central mismatch-recognition module with the conserved Phe‑X‑Glu motif that contacts mispaired bases and DNA distortions, and a C‑terminal ATPase domain harboring the Walker A and B motifs that support nucleotide binding and conformational switching within MutSα. MSH6 heterodimerizes with MSH2 to form MutSα, which surveys newly replicated or damaged DNA, recognizes single-base mismatches and small insertion–deletion loops, bends the helix, and shields a short stretch of DNA around the lesion while binding ADP; mismatch engagement triggers ADP–ATP exchange in the ATPase domains, converting MutSα into a sliding clamp that diffuses away from the original site and initiates communication with downstream repair factors. Interaction of ATP-loaded MutSα with MutLα (MLH1–PMS2) and with PCNA coordinates strand discrimination, excision, and resynthesis, and integrates mismatch repair with replication fork-associated processes. The PWWP domain in the MSH6 N terminus binds H3K36me3, recruiting MutSα to actively transcribed chromatin during G1 and early S phase and pre-positioning the complex on DNA that will undergo replication, which allows rapid detection of replication errors and contributes to genome-wide suppression of mutation accumulation. MSH6 functions as the lesion-binding subunit of MutSα and provides specificity toward single-base substitutions and small insertion–deletion events, while MSH2 supplies structural scaffolding and additional DNA-binding elements, and together they also participate in signaling from O⁶‑methylguanine–containing mismatches, promoting a DNA damage response that connects mismatch processing to checkpoint activation and apoptosis. MSH6 also associates with other repair and signaling factors, including Ku70 and related components, placing MutSα at points of crosstalk between mismatch repair, recombination, and double-strand break repair pathways. Germline and somatic pathogenic variants in MSH6 reduce or abolish MutSα function, lead to microsatellite instability and elevated rates of base substitution mutations with a bias toward mononucleotide repeat instability, and underlie a subset of Lynch syndrome (Lynch syndrome 5) and mismatch repair cancer syndrome, with strong associations to colorectal and endometrial carcinomas and a broader spectrum of tumors. |
Lane 1: 293T, Lane 2: COLO 205, Lane 3: COS-7, Lane 4: Vero
