Defects in mammalian DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, and MSH6) are characterized by microsatellite instability and reduced fidelity during replication and repair steps. The MMR proteins interact with each other to execute steps within the mismatch repair pathway. Defective variants of these proteins are associated with nonpolyposis colorectal cancer. The MutS proteins are thought to directly contact double-stranded DNA, scanning along the genomic DNA for mismatches analogous to a "sliding clamp" until they encounter a base pair containing a mismatch. The MutS proteins interact with multiple proteins including other MLH and MutL, the later have significant amino acid identify and structural similarity to the MLH proteins, as well as RPA, EXO1, RFC, possibly HMGB1, and other less well-characterized proteins.
With respect to the mutator function, the MSH2/MutSaplha heterodimer is thought primarily to repair single-base substitutions and 1 bp insertiondeletion mutations, while MSH2/MutSbeta is thought primarily to repair 1-4 bp insertiondeletion mutations. The MLH and MutL heterodimer proteins interact with heterodimers of MutS proteins to help catalyze different functions. MLH1:MutLalpha is the primary complex that interacts with both MutS alpha and beta complex in mechanisms thought to be relevant to cancer prevention. Recent studies suggest that MLH1:MLH3 may also contributes to some of these processes as well, but in all mechanisms tested to a lesser degree than MLH1:PMS2.
Heterozygous mutations in the MLH1 gene result in hereditary nonpolyposis colorectal cancer-2 (Papadopoulos et al., 1994).
Variants of the MSH2 gene are associated with hereditary nonpolyposis colorectal cancer. Alteration of MSH2 is also involved in Muir-Torre syndrome and mismatch repair cancer syndrome (Fishel et al. 1993).
Defects in the MSH3 gene are a cause of susceptibility to endometrial cancer (Risinger et al. 1996).
Defects in the MSH6 gene are less common than MLH1 and MSH2 defects. They have been mostly observed in atypical HNPCC families and are characterized by a weaker family history of tumor development, higher age at disease onset, and low degrees of microsatellite instability (MSI) (Lucci-Cordisco et al. 2001).
Mutations in the PMS2 gene are associated with hereditary nonpolyposis colorectal cancer, Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors. Heterozygous truncating mutations in PMS2 play a role in a small subset of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome, HNPCC-like) families. PMS2 mutations lead to microsatellite instability with carriers showing a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors (Hamilton et al. 1995, Hendriks et al. 2006).