DNA mismatch repair (MMR) is a DNA repair pathway that corrects incorrectly paired bases and small insertion–deletion loops in DNA, particularly errors left behind during DNA replication. It recognizes abnormal pairing, removes a segment of the error-containing strand, and replaces it using the complementary strand as a template. By preventing copying errors from becoming permanent mutations, MMR helps maintain genome stability. Its molecular machinery has been characterized through genetic studies and biochemical reconstruction with purified components. (pmc.ncbi.nlm.nih.gov)
Substrates and replication fidelity
Replication fidelity depends on successive safeguards. DNA polymerases select incoming nucleotides, and many replicative polymerases use proofreading to remove incorrectly incorporated nucleotides during synthesis. Mismatch repair acts on errors that escape these earlier controls. Its substrates include base–base mismatches, such as guanine paired with thymine, and loops containing unpaired nucleotides. Such loops can arise when the template and newly synthesized strands slip out of alignment in repetitive sequences. (nobelprize.org)
A mismatch does not necessarily involve a chemically damaged base: two otherwise normal bases can be paired incorrectly. MMR must therefore determine which strand contains the copying error rather than simply remove a damaged chemical group. Its reaction can replace a stretch of DNA extending beyond the mismatch itself. The essential sequence is mismatch recognition, strand discrimination, removal of the error-containing tract, repair synthesis, and sealing of the remaining break. (cmgm-new.stanford.edu)
The bacterial model
The best-characterized bacterial pathway is the methyl-directed system of Escherichia coli. The MutS protein recognizes a mismatch, while MutL coordinates subsequent reactions. MutH, an endonuclease, introduces a break in the strand selected for correction. These factors connect recognition of an abnormal base pair to processing at a separate strand-discrimination site. (cmgm-new.stanford.edu)
Strand choice depends on a temporary asymmetry in DNA methylation. At GATC sequences, the parental strand carries adenine methylation, whereas the newly synthesized strand is briefly unmethylated. MutH cuts the unmethylated strand. UvrD, a DNA helicase, and exonucleases then facilitate removal of a tract containing the mismatch; polymerase and DNA ligase restore the duplex. This methyl-directed arrangement is not universal among bacteria: many bacterial MutL proteins instead possess endonuclease activity, and their pathways do not require the same MutH-based system. (cmgm-new.stanford.edu)
Eukaryotic recognition complexes
In eukaryotes, MutS-related proteins form specialized complexes. Human MutSα consists of MSH2 and MSH6 and efficiently recognizes base–base mismatches and single-nucleotide insertion–deletion loops. MutSβ consists of MSH2 and MSH3 and preferentially processes larger small loops. Their substrate ranges overlap, so this division of labor is not absolute; biochemical assays demonstrate that both can repair some of the same insertion–deletion substrates. (pubmed.ncbi.nlm.nih.gov)
The principal human MutL complex, MutLα, comprises MLH1 and PMS2. PMS2 contains an endonuclease active site that allows the complex to introduce strand breaks during repair. Its activation requires coordinated interactions involving mismatch-recognition factors, replication-associated proteins, and ATP. Thus, eukaryotic MMR conserves the bacterial distinction between recognition and downstream processing while distributing those functions among different protein complexes. (pubmed.ncbi.nlm.nih.gov)
Strand discrimination and repair synthesis
Human mismatch repair does not use the E. coli GATC methylation signal. Experiments with defined DNA substrates show that a pre-existing strand discontinuity can direct repair to the interrupted strand. Proliferating cell nuclear antigen (PCNA), a sliding clamp associated with replication, and its loader, replication factor C, participate in coupling repair to strand discontinuities. PCNA also helps recruit mismatch-repair proteins to replicating DNA. (pmc.ncbi.nlm.nih.gov)
Activated MutLα introduces additional incisions preferentially into the discontinuous strand. EXO1, an exonuclease, can degrade DNA from an appropriate entry point through the mismatch-containing region. Replication protein A protects exposed single-stranded DNA and supports processing and synthesis. DNA polymerase δ fills the resulting gap, and ligation completes restoration of the strand. Purified-protein systems reproduce major steps of this reaction, although such systems simplify the organization and regulation found inside cells. (pubmed.ncbi.nlm.nih.gov)
Deficiency and human disease
Loss of mismatch-repair function increases the persistence of replication errors. A characteristic consequence is microsatellite instability (MSI): changes in the lengths of short repeated DNA sequences. MMR-deficient tumors can accumulate both base substitutions and insertion–deletion mutations. Deficiency is an important mechanism in the development of certain cancers, but it can arise through either inherited susceptibility or changes confined to tumor cells. (cancer.gov)
Lynch syndrome is associated with inherited pathogenic variants in the genes MLH1, MSH2, MSH6, or PMS2. Certain EPCAM deletions also cause Lynch syndrome by promoting silencing of neighboring MSH2. The syndrome increases susceptibility particularly to colorectal and endometrial cancer. Sporadic tumors may lose repair function through mechanisms such as MLH1 promoter methylation. Tumor mismatch-repair deficiency therefore does not, by itself, establish an inherited syndrome. (cancer.gov)
Experimental and clinical assessment
Laboratories assess mismatch-repair status using complementary methods. Immunohistochemistry examines the presence of MLH1, PMS2, MSH2, and MSH6 proteins in tumor tissue. MSI testing measures instability in selected repetitive DNA sequences, while molecular analysis can identify relevant sequence variants or methylation changes. These assays examine different aspects of the pathway—protein expression, its genomic consequences, and underlying alterations—and their results require contextual interpretation. (cancer.gov)
The experimental foundation includes reconstruction of E. coli mismatch correction with purified proteins in 1989 and later reconstruction of human strand-directed repair. Paul Modrich shared the 2015 Nobel Prize in Chemistry with Tomas Lindahl and Aziz Sancar for mechanistic studies of DNA repair; his contribution centered on mismatch repair. (scholars.duke.edu)