MSH6

MSH6 is a gene that encodes a DNA mismatch repair protein in eukaryotes. In humans and many other organisms, the MSH6 protein partners with MSH2 to form the MutSα complex, which recognizes base-base mismatches and small insertion–deletion loops that arise during DNA replication. The MutSα complex then coordinates repair by recruiting MutLα (MLH1-PMS2) and through downstream factors such as Exonuclease 1, DNA polymerase, and ligase to restore the correct sequence, thereby maintaining genome stability. MSH6 has a preference for single-base mismatches and small indels, while the MutSβ complex (MSH2-MSH3) handles larger insertion–deletion events.

MSH6 is a nuclear protein with a domain structure that includes an N-terminal mismatch recognition region, a connecting/lever region, and a C-terminal ATPase domain. It also contains a PCNA-interacting motif that helps tether the repair machinery to replication forks, linking mismatch repair to DNA replication. In humans, the MSH6 gene is located on chromosome 2p16.3, and the protein is approximately 1360 amino acids in length.

Clinical significance of MSH6 mutations includes predisposition to Lynch syndrome (hereditary nonpolyposis colorectal cancer), with a cancer spectrum that often includes colorectal and endometrial cancers and variable penetrance. Biallelic germline mutations in MSH6 cause constitutional mismatch repair deficiency (CMMRD), a rare and early-onset cancer predisposition syndrome often associated with high tumor mutational burden and other features. MSH6 alterations are one component of the broader mismatch repair deficiency landscape used in diagnostic and therapeutic planning.