Diseases of Mismatch Repair (MMR)

Stable Identifier
Homo sapiens
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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.

Literature References
PubMed ID Title Journal Year
16464822 Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis

Chao, EC, Lipkin, SM

Nucleic Acids Res. 2006
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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