MMRgenen

MMRgenen, or mismatch repair genes, encode proteins that correct DNA replication errors and thereby maintain genome stability. In humans and other eukaryotes, the core components are the MutS and MutL homologs. The MutS homologs MSH2, MSH3, and MSH6 form heterodimers that recognize mismatches and insertion-deletion loops: MSH2-MSH6 (MutSα) mainly targets base-base mismatches and small loops, while MSH2-MSH3 (MutSβ) recognizes larger insertion-deletion loops. The MutL homologs MLH1 forms heterodimers with PMS2 (MutLα) and MLH3 (MutLγ), which coordinate downstream repair steps including strand discrimination, excision, resynthesis, and ligation. Exonuclease Exo1 and the replication factors PCNA and RFC assist in the repair process. The pathway is linked to signaling pathways that can trigger cell-cycle arrest or apoptosis if damage is extensive.

Defects in MMR genes cause increased mutation rates and cancer susceptibility. Germline mutations in MLH1, MSH2, MSH6, and PMS2 are associated with Lynch syndrome, a hereditary colorectal and other cancer predisposition. Sporadic cancers often involve promoter hypermethylation of MLH1 or somatic mutations in MMR genes, leading to microsatellite instability (MSI). MMR status is routinely assessed in tumors for prognosis and to guide therapies such as immunotherapy.

MMRgenen are highly conserved and present across bacteria, archaea, and eukaryotes. In bacteria, MutS and MutL perform analogous roles with MutH providing strand discrimination in some species.