Mismatch Repair Genes


The mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The primary role of MMR is to correct errors such as base/base mismatches and small insertions/deletions that arise during DNA (deoxyribonucleic acid) synthesis. Loss of functional MMR results in increased rates of point mutations and microsatellite instability. Post‐replicative MMR is strand‐specific and serves mutation avoidance. Outside replication, discrimination between old and newly synthesised DNA strands is no longer necessary, and the MMR system can be mutagenic. Such non‐canonical actions of MMR are required, for example, for the generation of immunoglobulin diversity. The anti‐mutator and mutator activities of MMR play important roles in human diseases. Notably, germline mutations in MMR genes cause predisposition to Lynch syndrome, whereas epigenetic inactivation of the MMR gene MLH1 underlies 15% of sporadic colorectal and other cancers.

Key Concepts

  • Post‐replicative mismatch repair can counteract or promote mutations.
  • DNA mismatch repair genes are conserved in evolution.
  • DNA mismatch repair genes comply with Knudson's two‐hit paradigm for tumour suppressor genes.
  • Deficient DNA mismatch repair is responsible for microsatellite instability in tumours.
  • Inherited defects in DNA mismatch repair underlie Lynch syndrome, a dominant predisposition to colorectal, endometrial and other cancers.

Keywords: DNA mismatch repair; Lynch syndrome; hereditary nonpolyposis colon cancer; microsatellite instability; MutL; MutS; MLH1; MSH2; MSH6; PMS2

Figure 1. Scheme of human MMR. Single nucleotide mismatches are recognised by hMutSα (hMSH2 + hMSH6), whereas insertion–deletion loops are predominantly recognised by hMutSß (hMSH2 + hMSH3). hMutLα (hMLH1 + hPMS2) or hMutLγ (hMLH1 + hMLH3) for some insertion–deletion loops contributes to the assembly of a larger complex of MMR proteins enabling at least PCNA, RFC, RPA, EXO1, DNA polymerases and ligase to contribute to the removal of the error.
Figure 2. A graph showing the frequency and types of unique mutations in the Lynch syndrome genes MLH1, MSH2, MSH6 and PMS2. Based on data given in Plazzer et al. .


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Further Reading

Begum R and Martin SA (2016) Targeting mismatch repair defects: a novel strategy for personalized cancer treatment. DNA Repair (Amst) 38: 135–139.

Crouse GF (2016) Non‐canonical actions of mismatch repair. DNA Repair (Amst) 38: 102–109.

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Kansikas M, Kariola R and Nyström M (2011) Verification of the three‐step model in assessing the pathogenicity of mismatch repair gene variants. Human Mutation 32: 107–115.

Kunkel TA and Erie DA (2015) Eukaryotic Mismatch Repair in Relation to DNA Replication. Annual Review of Genetics 49: 291–313.

Li G‐M (2013) Decoding the histone code: role of H3K36me3 in mismatch repair and implications for cancer susceptibility and therapy. Cancer Research 73: 6379–6383.

Modrich P (2016) Mechanisms in E. coli and Human Mismatch Repair (Nobel Lecture). Angewandte Chemie International Edition in English 55: 8490–8501.

Møller P, Seppälä T, Bernstein I, et al. (2017) Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 66: 464–472.

Peltomäki P (2016) Update on Lynch Syndrome genomics. Familial Cancer 15: 385–393.

Web Link

The International Society for Gastrointestinal Hereditary Tumours (InSiGHT). Link: https://www.insight‐group.org/

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Kansikas, Minttu, Nyström, Minna, and Peltomäki, Päivi(Sep 2017) Mismatch Repair Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006045.pub2]