Human Mismatch Repair: Defects and Predisposition to Cancer

Abstract

Mismatch repair edits DNA replication and reduces spontaneous mutation rates. Individuals with inherited mutations in a mismatch repair gene are susceptible to cancer, and the absence of mismatch repair renders their tumours resistant to some anticancer drugs.

Keywords: hereditary nonpolyposis colorectal cancer; mutator phenotype; microsatellite instability; DNA damage tolerance; alkylating agents; cisplatin

Figure 1.

Likely steps in human mismatch correction. Errors committed during replication (A/C mispair, slipped/mispaired G, GT, GTC, or GTCA which form extrahelical loops) are recognized and bound by either hMutSα or hMutSβ as indicated. The hMutLα heterodimer is then recruited. This may possibly follow movement of the mismatched DNA through the bound heterodimer in a translocation process that is dependent on ATP hydrolysis. The mismatched segment is removed by hEXO1 or a similar activity with the reverse polarity. By analogy to mismatch repair in prokaryotes and to other repair pathways in human cells, a DNA helicase is likely to be involved in displacing the mispaired strand. The excised region is resynthesized by either DNA polymerase δ or ε both of which require PCNA as a processivity factor. Repair is completed by ligation of the newly synthesized patch to the original DNA strand. There is evidence to suggest that PCNA is actually recruited to the repair complex at an early stage as indicated.

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References

Buremeyer AB, Deschenes SM, Baker SM and Liskay RM (1999) Mammalian DNA mismatch repair. Annual Review of Genetics 33: 533–564.

Jamieson ER and Lippard SJ (1999) Structure, recognition, and processing of cisplatin–DNA adducts. Chemical Reviews 99: 2467–2498.

Karran P and Bignami M (1992) Self‐destruction and tolerance in resistance of mammalian cells to alkylation damage. Nucleic Acids Research 20: 2933–2940.

Karran P and Bignami M (1994) DNA damage tolerance, mismatch repair and genome instability. BioEssays 16: 833–839.

Karran P and Hampson R (1996) Genomic instability and tolerance to alkylating agents. Cancer Surveys 28: 69–85.

Lipkin SM, Wang V, Jacoby R et al. (2000) MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nature Genetics 24: 27–35.

Lynch HT, Watson P, Smyrk TC et al. (1991) Colon cancer genetics. Cancer 70: 1300–1312.

Modrich P and Lahue R (1996) Mismatch repair in replication fidelity, genetic recombination and cancer biology. Annual Review of Biochemistry 65: 101–133.

Pegg AE (1990) Mammalian O6‐alkylguanine‐DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Research 50: 6119–6129.

Perucho M (1996) The mutator that mutates other mutators. Nature Genetics 2: 630–631.

Perucho M (1999) Correspondence. Cancer Research 59: 249–256.

Ricciardone MD, Ozcelik T, Cevher B et al. (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type I. Cancer Research 59: 290–293.

Rodriguez‐Bigas MA, Boland CR, Hamilton SR et al. (1997) A National Cancer Institute workshop on Hereditary Non‐Polyposis Colorectal Cancer Syndrome: Meeting highlights and Bethesda guidelines. Journal of the National Cancer Institute 89: 1758–1762.

Schmutte C, Marinescu RC, Sadoff MM et al. (1998) Human exonuclease I interact with mismatch repair protein hMSH2. Cancer Research 58: 4537–4542.

Wang Q, Lasset C, Desseigne F et al. (1999) Neurofibromatosis and early onset cancers in hMLH1‐deficient children. Cancer Research 59: 294–297.

Watson P and Lynch HT (1993) Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71: 677–685.

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How to Cite close
Karran, Peter(Apr 2001) Human Mismatch Repair: Defects and Predisposition to Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0000572]