Päivi Peltomäki, University of Helsinki, Helsinki, Finland
Minna Nyström‐Lahti, University of Helsinki, Helsinki, Finland
Published online: January 2006
DOI: 10.1038/npg.els.0006045
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 synthesis and recombination.
Keywords: DNA mismatch repair; hereditary nonpolyposis colon cancer; microsatellite instability; MutL; MutS
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Figure 1. Scheme of human MMR. The precise steps in which proliferating cell nuclear antigen (PCNA), replication factor C (RFC) and single-stranded DNA-binding protein (RPA) become involved are not known. EXO1: exonuclease 1; FEN1: endo/exonuclease homologous to yeast RAD27.
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Figure 2. Diagram showing how HNPCC-associated mutations disrupt the functional domains of the MSH2 (a) and MLH1 (b) gene products. In (a) the putative DNA binding regions of MSH2 are shown with light shading and the proposed ATPase domain is the dark region.
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| References | |
| Ban C and Yang W (1998) Crystal structure and ATPase activity of MutL: implications for DNA repair and mutagenesis. Cell 95: 541–552. | |
| Bhattacharyya NP, Skandalis A, Ganesh A, Groden J and Meuth M (1994) Mutator phenotypes in human colorectal carcinoma cells. Proceedings of the National Academy of Sciences of the United States of America 91: 6319–6323. | |
| Boland CR, Thibodeau SN, Hamilton SR, et al. (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Research 58: 5248–5257. | |
| Bowers J, Tran PT, Joshi A, Liskay RM and Alani E (2001) MSH–MLH complexes formed at a DNA mismatch are disrupted by the PCNA sliding clamp. Journal of Molecular Biology 306: 957–968. | |
| Fishel R (2001) The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. Cancer Research 61: 7369–7374. | |
| Ionov Y, Peinado MA, Malkhosyan S, Shibata D and Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363: 558–561. | |
| Lamers MH, Perrakis A, Enzlin JH, et al. (2000) The crystal structure of DNA mismatch repair protein MutS binding to a G/T mismatch. Nature 407: 711–717. | |
| Obmolova G, Ban C, Hsieh P and Yang W (2000) Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature 407: 703–710. | |
| Peltomäki P, Vasen HFA and the International Collaborative Group on HNPCC (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology 113: 1146–1158. | |
| Umar A, Buermeyer AB, Simon JA, et al. (1996) Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87: 65–73. | |
| Further Reading | |
| Buermeyer AB, Deschenes SM, Baker SM and Liskay RM (1999) Mammalian DNA mismatch repair. Annual Review of Genetics 33: 533–564. | |
| Guerrette S, Acharya S and Fishel R (1999) The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. Journal of Biological Chemistry 274: 6336–6341. | |
| Guerrette S, Wilson T, Gradia S and Fishel R (1998) Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer. Molecular and Cellular Biology 18: 6616–6623. | |
| Jiricny J and Nyström-Lahti M (2000) Mismatch repair defects in cancer. Current Opinion in Genetics and Development 10: 157–161. | |
| Kolodner RD and Marsischky GT (1999) Eukaryotic mismatch repair. Current Opinion in Genetics and Development 9: 89–96. | |
| Lynch HT and de la Chapelle A (1999) Genetic susceptibility to non-polyposis colorectal cancer. Journal of Medical Genetics 36: 801–818. | |
| Marti TM, Kunz C and Fleck O (2002) DNA mismatch repair and mutation avoidance pathways. Journal of Cellular Physiology 191: 28–41. | |
| Modrich P (1991) Mechanisms and biological effects of mismatch repair. Annual Review of Genetics 25: 229–253. | |
| Pang Q, Prolla TA and Liskay RM (1997) Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations. Molecular and Cellular Biology 17: 4465–4473. | |
| Peltomäki P, Aaltonen LA, Sistonen P, et al. (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260: 810–812. | |
| Web Links | |
| ePath International Collaborative Group on HNPCC. The mutation database of this website contains information of pathogenic, HNPCC-associated mutations as well as polymorphisms observed in MMR genes http://www.nfdht.nl | |
| ePath Hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome) (HPRT1); Locus ID: 3251. LocusLink:. http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?=3251 | |
| ePath mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); Locus ID: 4292. LocusLink:. http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?=4292 | |
| ePath http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?=4436 mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); Locus ID: 4436. LocusLink:. | |
| ePath mutS homolog 6 (E. coli) (MSH6); Locus ID: 2956. LocusLink:. http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?=2956 | |
| ePath PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2); Locus ID: 5395. LocusLink:. http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?=5395 | |
| ePath Hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome) (HPRT1); MIM number: 308000. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?308000 | |
| ePath mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); MIM number: 120436. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?120436 | |
| ePath mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); MIM number: 120435. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?120435 | |
| ePath mutS homolog 6 (E. coli) (MSH6); MIM number: 600678. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600678 | |
| ePath PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2); MIM number: 600259. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600259 | |
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