Definition: Mismatch repair (MMR) is a biochemical process dedicated primarily to the excision of nucleotides that are incorrectly paired with the (correct) nucleotide on the opposite DNA strand.
Mispairing most frequently (but not exclusively) transpires during DNA replication because of the limited fidelity of the DNA replicative machinery. Hence, the incorrect base occurs in the newly synthesized DNA strand. All cells have specific mechanisms by which they discriminate between newly replicated and parental DNA strands.
However, the precise mechanism of strand discrimination in eukaryotic cells is not known. In human cells, the recognition of small loops generated by insertion or deletion of nucleotides, as well as single base mismatches (A:X), is primarily accomplished by a complex called MUTS - a heterodimer of MSH2 and MSH6. Another heterodimer, MUTS, comprising MSH2 and MSH3, can also operate in the recognition of small loops during MMR.
The precise biochemical events subsequent to mismatch recognition in mammalian cells are not well understood, but are believed to involve other heterodimeric complexes, comprising proteins called MLH1, PMS2 and MLH3.
As is the case with defective NER (nucleotide excision system), defects in MMR in humans predispose to cancer, in this case primarily to colon cancer but also to uterine, ovarian and gastric cancer.
Pathogeny
When DNA damage temporarily overwhelms mammalian lesion-removal systems, error-prone replication past unrepaired lesions can generate mutations, cell-cycle arrest can provide more time to remove lesions, and programmed death (apoptosis) can eliminate hopelessly damaged cells.
Mismatch-repair (MMR) systems frequently suppress mutations generated by bypass polymerases and help signal to checkpoint and apoptosis pathways.
Thus, the cancer predisposition of human beings with defective MMR genes may reflect deficiencies in some or all of these responses to DNA damage, as well as increased spontaneous mutation due to impaired correction of replication errors (base-mismatches).
Also, the efficacy of certain anti-tumour drugs depends on MMR-mediated apoptosis.
The DNA lesions are induced by sunlight (UV photoproducts), endogenous oxygen metabolism (8-oxoguanine and other oxidized purines), cooked-meat heterocyclic amines, and anti-cancer and immunosuppressant drugs (O6-methylguanine, G[cisplatin]G crosslinks), or ionizing radiation (DNA breaks).
Pathogeny
A cause for genetic instability is the frequent appearance of mismatches on the double helix of DNA. Base-base mismatches and small loops may occur during most of the main mechanism that process DNA, that is, replication, recombination and repair itself.
From bacteria to eukaryotes, there are special enzymatic machineries that correct these mismatches, restoring the original DNA sequence, which are generally called DNA mismatch repair.
Defects on DNA repair in bacteria have long been known as a cause for a mutator phenotype. Thus, such a phenotype would be also expected in human cells, and it could also be related to hereditary cancer.
In fact, one of the most interesting recent findings in the field was the discovery that mutations in mismatch repair genes (such as MSH2, MLH1, PMS1 and PMS2) are responsible for the hereditary nonpolyposis colorectal cancer (HNPCC), which affects as many as 1 in 200 individuals, and also a subset of sporadic colorectal cancers.
Individuals are normally heterozygous for the mismatch genes, but the loss of heterozygosity, that may occur spontaneously, leads to genetic instability, originating tumor cells.
In fact, cells from tumors of HNPCC patients show increased microsatellite instability and are normally defective for DNA mismatch repair.
As for the ATM gene, the availability of the DNA mismatch repair gene sequences will aid the screening of HNPCC families for the most frequent mutated alleles.
Moreover, other types of sporadic cancers are found to be associated with the instability of microsatellite DNA sequences, probably due to a deficient mismatch repair.
Colorectal tumorigenesis
Mismatch repair (MMR) deficiency is a major mechanism of colorectal tumorigenesis that is observed in 10-15% of sporadic colorectal cancers and those associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.
Coding microsatellites (cMS)
MMR deficiency leads to the accumulation of mutations mainly at short repetitive sequences termed microsatellites, constituting the high level microsatellite instability (MSI-H) phenotype.
In recent years, several genes have been described that harbor microsatellites in their coding region (coding microsatellites, cMS) and are frequently affected by mutations in MMR-deficient cancers.
However, evidence for a functional role of most of the known cMS-containing genes is missing, and further analyses are needed for a better understanding of MSI tumorigenesis.
DNA mismatch repair proteins
| MLH1 | MSH2 | MSH6 | PMS1 | PMS2 |
Pathology: HNPCC syndromes, mismatch repair deficiency
| genes | MIM | Disease | Loc. | MIM |
| MLH1 | MIM.120436 | HNPCC2 | 3p21.3 | MIM.609310 |
| MLH3 | MIM.604395 | HNPCC7 | 14q24.3 | MIM.604395 |
| MSH2 | MIM.609309 | HNPCC1 | 2p22-p21 | MIM.120435 |
| MSH6 | MIM.600678 | HNPCC5 | 2p16 | MIM.600678 |
| PMS1 | MIM.600258 | HNPCC3 | 2q31-q33 | MIM.600258 |
| PMS2 | MIM.600259 | HNPCC4 | 7p22 | MIM.600259 |
| TGFBR2 | MIM.190182 | HNPCC6 | 3p22 | MIM.190182 |
By localization
mismatch repair in colonic carcinoma
mismatch repair in gastric carcinoma
References
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