Journal of Molecular Histology

, Volume 37, Issue 5–7, pp 271–283 | Cite as

DNA mismatch repair and Lynch syndrome

  • Guido PlotzEmail author
  • Stefan Zeuzem
  • Jochen Raedle


The evolutionary conserved mismatch repair proteins correct a wide range of DNA replication errors. Their importance as guardians of genetic integrity is reflected by the tremendous decrease of replication fidelity (two to three orders of magnitude) conferred by their loss. Germline mutations in mismatch repair genes, predominantly MSH2 and MLH1, have been found to underlie the Lynch syndrome (also called hereditary non-polyposis colorectal cancer, HNPCC), a hereditary predisposition for cancer. Lynch syndrome affects predominantly the colon and accounts for 2–5% of all colon cancer cases. During more than 30 years of biochemical, crystallographic and clinical research, deep insight has been achieved in the function of mismatch repair and the diseases that are associated with its loss. We review the biochemistry of mismatch repair and also introduce the clinical, diagnostic and genetic aspects of Lynch syndrome.


Mismatch repair Lynch syndrome HNPCC Hereditary non-polyposis colorectal cancer MSH2 MLH1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



We would like to apologize to all authors whose work could not be cited here due to space limitations. This work was supported by the HOMFOR Grant A/2004/13 to G.P. and by the Marianne and Klaus Paschke grant of the Freunde der Universität des Saarlandes to J.R.


  1. Acharya S, Foster PL, Brooks P, Fishel R (2003) The coordinated functions of the E. coli MutS and MutL proteins in mismatch repair. Mol Cell 12:233–246PubMedGoogle Scholar
  2. Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R (1996) hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci USA 93:13629–13634PubMedGoogle Scholar
  3. Akrami SM, Dunlop MG, Farrington SM, Frayling IM, Macdonald F, Harvey JF, Armour JA (2005) Screening for exonic copy number mutations at MSH2 and MLH1 by MAPH. Fam Cancer 4:145–149PubMedGoogle Scholar
  4. Alam NA, Gorman P, Jaeger EE, Kelsell D, Leigh IM, Ratnavel R, Murdoch ME, Houlston RS, Aaltonen LA, Roylance RR, Tomlinson IP (2003) Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability. Cancer Genet Cytogenet 147:121–127PubMedGoogle Scholar
  5. Alani E, Lee JY, Schofield MJ, Kijas AW, Hsieh P, Yang W (2003) Crystal structure and biochemical analysis of the MutS–ADP–beryllium fluoride complex suggests a conserved mechanism for ATP interactions in mismatch repair. J Biol Chem 278:16088–16094PubMedGoogle Scholar
  6. Allen DJ, Makhov A, Grilley M, Taylor J, Thresher R, Modrich P, Griffith JD (1997) MutS mediates heteroduplex loop formation by a translocation mechanism. EMBO J 16:4467–4476PubMedGoogle Scholar
  7. Ban C, Junop M, Yang W (1999) Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. Cell 97:85–97PubMedGoogle Scholar
  8. Ban C, Yang W (1998a) Crystal structure and ATPase activity of MutL: implications for DNA repair and mutagenesis. Cell 95:541–552Google Scholar
  9. Ban C, Yang W (1998b) Structural basis for MutH activation in E. coli mismatch repair and relationship of MutH to restriction endonucleases. EMBO J 17:1526–1534Google Scholar
  10. Baudhuin LM, Ferber MJ, Winters JL, Steenblock KJ, Swanson RL, French AJ, Butz ML, Thibodeau SN (2005) Characterization of hMLH1 and hMSH2 gene dosage alterations in Lynch syndrome patients. Gastroenterology 129:846–854PubMedGoogle Scholar
  11. Bende SM, Grafstrom RH (1991) The DNA binding properties of the MutL protein isolated from Escherichia coli. Nucleic Acids Res 19:1549–1555PubMedGoogle Scholar
  12. Blackwell LJ, Martik D, Bjornson KP, Bjornson ES, Modrich P (1998) Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism. J Biol Chem 273:32055–32062PubMedGoogle Scholar
  13. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (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 Res 58:5248–5257PubMedGoogle Scholar
  14. Bonthron DT, Hayward BE, De Vos M, Sheridan E (2005) PMS2 mutations in childhood cancer. Gut 54:1821PubMedGoogle Scholar
  15. Bowers J, Sokolsky T, Quach T, Alani E (1999) A mutation in the MSH6 subunit of the Saccharomyces cerevisiae MSH2- MSH6 complex disrupts mismatch recognition. J Biol Chem 274:16115–16125PubMedGoogle Scholar
  16. Brieger A, Trojan J, Raedle J, Plotz G, Zeuzem S (2002) Transient mismatch repair gene transfection for functional analysis of genetic hMLH1 and hMSH2 variants. Gut 51:677–684PubMedGoogle Scholar
  17. Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368:258–261PubMedGoogle Scholar
  18. Bruni R, Martin D, Jiricny J (1988) d(GATC) sequences influence Escherichia coli mismatch repair in a distance-dependent manner from positions both upstream and downstream of the mismatch. Nucleic Acids Res 16:4875–4890PubMedGoogle Scholar
  19. Cannavo E, Marra G, Sabates-Bellver J, Menigatti M, Lipkin SM, Fischer F, Cejka P, Jiricny J (2005) Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair. Cancer Res 65:10759–10766PubMedGoogle Scholar
  20. Chao EC, Lipkin SM (2006) Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res 34:840–852PubMedGoogle Scholar
  21. Chen PC, Dudley S, Hagen W, Dizon D, Paxton L, Reichow D, Yoon SR, Yang K, Arnheim N, Liskay RM, Lipkin SM (2005) Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Res 65:8662–8670PubMedGoogle Scholar
  22. Clark AB, Valle F, Drotschmann K, Gary RK, Kunkel TA (2000) Functional interaction of proliferating cell nuclear antigen with MSH2–MSH6 and MSH2–MSH3 complexes. J Biol Chem 275:36498–36501PubMedGoogle Scholar
  23. Claverys JP, Lacks SA (1986) Heteroduplex deoxyribonucleic acid base mismatch repair in bacteria. Microbiol Rev 50:133–165PubMedGoogle Scholar
  24. Constantin N, Dzantiev L, Kadyrov FA, Modrich P (2005) Human mismatch repair: reconstitution of a nick-directed bidirectional reaction. J Biol Chem 280:39752–39761PubMedGoogle Scholar
  25. Cooper DL, Lahue RS, Modrich P (1993) Methyl-directed mismatch repair is bidirectional. J Biol Chem 268:11823–11829PubMedGoogle Scholar
  26. Corrette-Bennett SE, Lahue RS (1999) Mismatch repair assay. Methods Mol Biol 113:121–132PubMedGoogle Scholar
  27. De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964PubMedGoogle Scholar
  28. Drotschmann K, Hall MC, Shcherbakova PV, Wang H, Erie DA, Brownewell FR, Kool ET, Kunkel TA (2002) DNA binding properties of the yeast Msh2–Msh6 and Mlh1–Pms1 heterodimers. Biol Chem 383:969–975PubMedGoogle Scholar
  29. Drummond JT, Bellacosa A (2001) Human DNA mismatch repair in vitro operates independently of methylation status at CpG sites. Nucleic Acids Res 29:2234–2243PubMedGoogle Scholar
  30. Drummond JT, Li GM, Longley MJ, Modrich P (1995) Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 268:1909–1912PubMedGoogle Scholar
  31. Dufner P, Marra G, Raschle M, Jiricny J (2000) Mismatch recognition and DNA-dependent stimulation of the ATPase activity of hMutSalpha is abolished by a single mutation in the hMSH6 subunit. J Biol Chem 275:36550–36555PubMedGoogle Scholar
  32. Dutta R, Inouye M (2000) GHKL, an emergent ATPase/kinase superfamily. Trends Biochem Sci 25:24–28PubMedGoogle Scholar
  33. Dzantiev L, Constantin N, Genschel J, Iyer RR, Burgers PM, Modrich P (2004) A defined human system that supports bidirectional mismatch-provoked excision. Mol Cell 15:31–41PubMedGoogle Scholar
  34. Erdeniz N, Dudley S, Gealy R, Jinks-Robertson S, Liskay RM (2005) Novel PMS1 alleles preferentially affect the repair of primer strand loops during DNA replication. Mol Cell Biol 25:9221–9231PubMedGoogle Scholar
  35. Fang WH, Modrich P (1993) Human strand-specific mismatch repair occurs by a bidirectional mechanism similar to that of the bacterial reaction. J Biol Chem 268:11838–11844PubMedGoogle Scholar
  36. Fishel R, Ewel A, Lee S, Lescoe MK, Griffith J (1994) Binding of mismatched microsatellite DNA sequences by the human MSH2 protein. Science 266:1403–1405PubMedGoogle Scholar
  37. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038PubMedGoogle Scholar
  38. Flores-Rozas H, Clark D, Kolodner RD (2000) Proliferating cell nuclear antigen and Msh2p–Msh6p interact to form an active mispair recognition complex. Nat Genet 26:375–378PubMedGoogle Scholar
  39. Genschel J, Littman SJ, Drummond JT, Modrich P (1998) Isolation of MutSbeta from human cells and comparison of the mismatch repair specificities of MutSbeta and MutSalpha. J Biol Chem 273:19895–19901PubMedGoogle Scholar
  40. Giron-Monzon L, Manelyte L, Ahrends R, Kirsch D, Spengler B, Friedhoff P (2004) Mapping protein–protein interactions between MutL and MutH by cross-linking. J Biol Chem 279:49338–49345PubMedGoogle Scholar
  41. Gradia S, Acharya S, Fishel R (1997) The human mismatch recognition complex hMSH2–hMSH6 functions as a novel molecular switch. Cell 91:995–1005PubMedGoogle Scholar
  42. Grilley M, Griffith J, Modrich P (1993) Bidirectional excision in methyl-directed mismatch repair. J Biol Chem 268:11830–11837PubMedGoogle Scholar
  43. Grilley M, Welsh KM, Su SS, Modrich P (1989) Isolation and characterization of the Escherichia coli mutL gene product. J Biol Chem 264:1000–1004PubMedGoogle Scholar
  44. Guarne A, Junop MS, Yang W (2001) Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. EMBO J 20:5521–5531PubMedGoogle Scholar
  45. Guarne A, Ramon-Maiques S, Wolff EM, Ghirlando R, Hu X, Miller JH, Yang W (2004) Structure of the MutL C-terminal domain: a model of intact MutL and its roles in mismatch repair. EMBO J 23:4134–4145Google Scholar
  46. Guerrette S, Acharya S, Fishel R (1999) The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem 274:6336–6341PubMedGoogle Scholar
  47. Hall MC, Jordan JR, Matson SW (1998) Evidence for a physical interaction between the Escherichia coli methyl-directed mismatch repair proteins MutL and UvrD. EMBO J 17:1535–1541PubMedGoogle Scholar
  48. Hall MC, Matson SW (1999) The Escherichia coli MutL protein physically interacts with MutH and stimulates the MutH-associated endonuclease activity. J Biol Chem 274:1306–1312PubMedGoogle Scholar
  49. Hall MC, Wang H, Erie DA, Kunkel TA (2001) High affinity cooperative DNA binding by the yeast Mlh1–Pms1 heterodimer. J Mol Biol 312:637–647PubMedGoogle Scholar
  50. Hendriks YM, Jagmohan-Changur S, Van Der Klift HM, Morreau H, Van Puijenbroek M, Tops C, Van Os T, Wagner A, Ausems MG, Gomez E, Breuning MH, Brocker-Vriends AH, Vasen HF, Wijnen JT (2006) Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch Syndrome). Gastroenterology 130:312–322PubMedGoogle Scholar
  51. Holmes J Jr, Clark S, Modrich P (1990) Strand-specific mismatch correction in nuclear extracts of human and Drosophila melanogaster cell lines. Proc Natl Acad Sci USA 87:5837–5841PubMedGoogle Scholar
  52. Iyer RR, Pluciennik A, Burdett V, Modrich PL (2006) DNA mismatch repair: functions and mechanisms. Chem Rev 106:302–323PubMedGoogle Scholar
  53. Jagmohan-Changur S, Poikonen T, Vilkki S, Launonen V, Wikman F, Orntoft TF, Moller P, Vasen H, Tops C, Kolodner RD, Mecklin JP, Jarvinen H, Bevan S, Houlston RS, Aaltonen LA, Fodde R, Wijnen J, Karhu A (2003) EXO1 variants occur commonly in normal population: evidence against a role in hereditary nonpolyposis colorectal cancer. Cancer Res 63:154–158PubMedGoogle Scholar
  54. Jiricny J, Marra G (2003) DNA repair defects in colon cancer. Curr Opin Genet Dev 13:61–69PubMedGoogle Scholar
  55. Junop MS, Obmolova G, Rausch K, Hsieh P, Yang W (2001) Composite active site of an ABC ATPase: MutS uses ATP to verify mismatch recognition and authorize DNA repair. Mol Cell 7:1–12PubMedGoogle Scholar
  56. Kosinski J, Steindorf I, Bujnicki JM, Giron-Monzon L, Friedhoff P (2005) Analysis of the quaternary structure of the MutL C-terminal domain. J Mol Biol 351:895–909PubMedGoogle Scholar
  57. Kramer B, Kramer W, Fritz HJ (1984) Different base/base mismatches are corrected with different efficiencies by the methyl-directed DNA mismatch-repair system of E. coli. Cell 38:879–887PubMedGoogle Scholar
  58. Kunkel TA, Erie DA (2005) DNA mismatch repair. Annu Rev Biochem 74:681–710PubMedGoogle Scholar
  59. Lahue RS, Au KG, Modrich P (1989) DNA mismatch correction in a defined system. Science 245:160–164PubMedGoogle Scholar
  60. Lahue RS, Su SS, Modrich P (1987) Requirement for d(GATC) sequences in Escherichia coli mutHLS mismatch correction. Proc Natl Acad Sci USA 84:1482–1486PubMedGoogle Scholar
  61. Lamers MH, Georgijevic D, Lebbink JH, Winterwerp HH, Agianian B, De Wind N, Sixma TK (2004) ATP increases the affinity between MutS ATPase domains. Implications for ATP hydrolysis and conformational changes. J Biol Chem 279:43879–43885PubMedGoogle Scholar
  62. Lamers MH, Perrakis A, Enzlin JH, Winterwerp HH, De Wind N, Sixma TK (2000) The crystal structure of DNA mismatch repair protein MutS binding to a G x T mismatch. Nature 407:711–717PubMedGoogle Scholar
  63. Lamers MH, Winterwerp HH, Sixma TK (2003) The alternating ATPase domains of MutS control DNA mismatch repair. EMBO J 22:746–756PubMedGoogle Scholar
  64. Lebbink JH, Georgijevic D, Natrajan G, Fish A, Winterwerp HH, Sixma TK, De Wind N (2006) Dual role of MutS glutamate 38 in DNA mismatch discrimination and in the authorization of repair. EMBO J 25:409–419PubMedGoogle Scholar
  65. Lee SD, Alani E (2006) Analysis of Interactions Between Mismatch Repair Initiation Factors and the Replication Processivity Factor PCNA. J Mol Biol 355:175–184PubMedGoogle Scholar
  66. Levinson G, Gutman GA (1987) Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol Biol Evol 4:203–221PubMedGoogle Scholar
  67. Li GM, Wang H, Romano LJ (1996) Human MutSalpha specifically binds to DNA containing aminofluorene and acetylaminofluorene adducts. J Biol Chem 271:24084–24088PubMedGoogle Scholar
  68. Lin DP, Wang Y, Scherer SJ, Clark AB, Yang K, Avdievich E, Jin B, Werling U, Parris T, Kurihara N, Umar A, Kucherlapati R, Lipkin M, Kunkel TA, Edelmann W (2004) An Msh2 point mutation uncouples DNA mismatch repair and apoptosis. Cancer Res 64:517–522PubMedGoogle Scholar
  69. Lindblom A, Tannergard P, Werelius B, Nordenskjold M (1993) Genetic mapping of a second locus predisposing to hereditary non- polyposis colon cancer. Nat Genet 5:279–282PubMedGoogle Scholar
  70. Lipkin SM, Rozek LS, Rennert G, Yang W, Chen PC, Hacia J, Hunt N, Shin B, Fodor S, Kokoris M, Greenson JK, Fearon E, Lynch H, Collins F, Gruber SB (2004) The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nat Genet 36:694–699PubMedGoogle Scholar
  71. Lipkin SM, Wang V, Jacoby R, Banerjee-Basu S, Baxevanis AD, Lynch HT, Elliott RM, Collins FS (2000) MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat Genet 24:27–35PubMedGoogle Scholar
  72. Liu T, Tannergard P, Hackman P, Rubio C, Kressner U, Lindmark G, Hellgren D, Lambert B, Lindblom A (1999) Missense mutations in hMLH1 associated with colorectal cancer. Hum Genet 105:437–441PubMedGoogle Scholar
  73. Liu T, Yan H, Kuismanen S, Percesepe A, Bisgaard ML, Pedroni M, Benatti P, Kinzler KW, Vogelstein B, Ponz DL, Peltomaki P, Lindblom A (2001) The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. Cancer Res 61:7798–7802PubMedGoogle Scholar
  74. Lu AL, Clark S, Modrich P (1983) Methyl-directed repair of DNA base-pair mismatches in vitro. Proc Natl Acad Sci USA 80:4639–4643PubMedGoogle Scholar
  75. Lubomierski N, Plotz G, Wormek M, Engels K, Kriener S, Trojan J, Jungling B, Zeuzem S, Raedle J (2005) BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors. Cancer 104:952–961PubMedGoogle Scholar
  76. Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, Lynch JF, Barrows A, Wijnen J, Van Der Klift H, Franken P, Wagner A, Fodde R, De La Chapelle A (2004a) A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States. JAMA 291:718–724Google Scholar
  77. Lynch HT, Cristofaro G, Rozen P, Vasen H, Lynch P, Mecklin JP, St John J (2003) History of the International Collaborative Group on hereditary non polyposis colorectal cancer. Fam Cancer 2:3–5PubMedGoogle Scholar
  78. Lynch HT, De La Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932PubMedGoogle Scholar
  79. Lynch HT, Lynch JF (2004) Lynch syndrome: history and current status. Dis Markers 20:181–198PubMedGoogle Scholar
  80. Lynch HT, Riley BD, Weissman SM, Coronel SM, Kinarsky Y, Lynch JF, Shaw TG, Rubinstein WS (2004b) Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: problems in diagnosis, surveillance, and management. Cancer 100:53–64Google Scholar
  81. Lynch HT, Smyrk T, Lynch JF (1998) Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation. Oncology 55:103–108PubMedGoogle Scholar
  82. Mechanic LE, Frankel BA, Matson SW (2000) Escherichia coli MutL loads DNA helicase II onto DNA. J Biol Chem 275:38337–38346PubMedGoogle Scholar
  83. Mello JA, Acharya S, Fishel R, Essigmann JM (1996) The mismatch-repair protein hMSH2 binds selectively to DNA adducts of the anticancer drug cisplatin. Chem Biol 3:579–589PubMedGoogle Scholar
  84. Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T (1997) Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer Nat Genet 17:271–272PubMedGoogle Scholar
  85. Nakagawa H, Lockman JC, Frankel WL, Hampel H, Steenblock K, Burgart LJ, Thibodeau SN, De La Chapelle A (2004) Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 64:4721–4727PubMedGoogle Scholar
  86. Natrajan G, Lamers MH, Enzlin JH, Winterwerp HH, Perrakis A, Sixma TK (2003) Structures of Escherichia coli DNA mismatch repair enzyme MutS in complex with different mismatches: a common recognition mode for diverse substrates. Nucleic Acids Res 31:4814–4821PubMedGoogle Scholar
  87. Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM (1994) Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80PubMedGoogle Scholar
  88. Nystrom-Lahti M, Kristo P, Nicolaides NC, Chang SY, Aaltonen LA, Moisio AL, Jarvinen HJ, Mecklin JP, Kinzler KW, Vogelstein B et al (1995) Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat Med 1:1203–1206PubMedGoogle Scholar
  89. Nystrom-Lahti M, Perrera C, Raschle M, Panyushkina-Seiler E, Marra G, Curci A, Quaresima B, Costanzo F, D’urso M, Venuta S, Jiricny J (2002) Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. Genes Chromosomes Cancer 33:160–167PubMedGoogle Scholar
  90. Obmolova G, Ban C, Hsieh P, Yang W (2000) Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature 407:703–710PubMedGoogle Scholar
  91. Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes M, D’arrigo A, Truong O, Hsuan JJ, Jiricny J (1995) GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268:1912–1914PubMedGoogle Scholar
  92. Palombo F, Iaccarino I, Nakajima E, Ikejima M, Shimada T, Jiricny J (1996) hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr Biol 6:1181–1184PubMedGoogle Scholar
  93. Pang PP, Lundberg AS, Walker GC (1985) Identification and characterization of the mutL and mutS gene products of Salmonella typhimurium LT2. J Bacteriol 163:1007–1015PubMedGoogle Scholar
  94. Pang PP, Tsen SD, Lundberg AS, Walker GC (1984) The mutH, mutL, mutS, and uvrD genes of Salmonella typhimurium LT2. Cold Spring Harb Symp Quant Biol 49:597–602PubMedGoogle Scholar
  95. Papadopoulos N, Nicolaides NC, Liu B, Parsons R, Lengauer C, Palombo F, D’arrigo A, Markowitz S, Willson JK, Kinzler KW (1995) Mutations of GTBP in genetically unstable cells. Science 268:1915–1917PubMedGoogle Scholar
  96. Peltomaki P (2005) Lynch syndrome genes. Fam Cancer 4:227–232PubMedGoogle Scholar
  97. Peltomaki P, Aaltonen LA, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Green JS, Jass JR, Weber JL, Leach FS (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812PubMedGoogle Scholar
  98. Peltomaki P, Vasen H (2004) Mutations associated with HNPCC predisposition – update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 20:269–276PubMedGoogle Scholar
  99. Plotz G, Piiper A, Wormek M, Zeuzem S, Raedle J (2006) Analysis of the human MutLalpha–MutSalpha complex. Biochem Biophys Res Commun 340:852–859PubMedGoogle Scholar
  100. Plotz G, Raedle J, Brieger A, Trojan J, Zeuzem S (2002) hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA. Nucleic Acids Res 30:711–718PubMedGoogle Scholar
  101. Plotz G, Raedle J, Brieger A, Trojan J, Zeuzem S (2003) N-terminus of hMLH1 confers interaction of hMutLalpha and hMutLbeta with hMutSalpha. Nucleic Acids Res 31:3217–3226PubMedGoogle Scholar
  102. Ponti G, Ponz De Leon M (2005) Muir-Torre syndrome. Lancet Oncol 6:980–987PubMedGoogle Scholar
  103. Prolla TA, Baker SM, Harris AC, Tsao JL, Yao X, Bronner CE, Zheng B, Gordon M, Reneker J, Arnheim N, Shibata D, Bradley A, Liskay RM (1998) Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair. Nat Genet 18:276–279PubMedGoogle Scholar
  104. Quaresima B, Alifano P, Tassone P, Avvedimento EV, Costanzo FS, Venuta S (2003) Human mismatch-repair protein MutL homologue 1 (MLH1) interacts with Escherichia coli MutL and MutS in vivo and in vitro: a simple genetic system to assay MLH1 function. Biochem J 371:183–189PubMedGoogle Scholar
  105. Raedle J, Trojan J, Brieger A, Weber N, Schafer D, Plotz G, Staib-Sebler E, Kriener S, Lorenz M, Zeuzem S (2001) Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer. Ann Intern Med 135:566–576PubMedGoogle Scholar
  106. Raschle M, Marra G, Nystrom-Lahti M, Schar P, Jiricny J (1999) Identification of hMutLbeta, a heterodimer of hMLH1 and hPMS1. J Biol Chem 274:32368–32375PubMedGoogle Scholar
  107. Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R (2001) The interaction of DNA mismatch repair proteins with human exonuclease I. J Biol Chem 276:33011–33018PubMedGoogle Scholar
  108. Schouten JP, Mcelgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57PubMedGoogle Scholar
  109. Sixma TK (2001) DNA mismatch repair: MutS structures bound to mismatches. Curr Opin Struct Biol 11:47–52PubMedGoogle Scholar
  110. Su SS, Modrich P (1986) Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs. Proc Natl Acad Sci USA 83:5057–5061PubMedGoogle Scholar
  111. Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819PubMedGoogle Scholar
  112. Thomas DC, Roberts JD, Kunkel TA (1991) Heteroduplex repair in extracts of human HeLa cells. J Biol Chem 266:3744–3751PubMedGoogle Scholar
  113. Tiraby JG, Fox MS (1973) Marker discrimination in transformation and mutation of pneumococcus. Proc Natl Acad Sci USA 70:3541–3545PubMedGoogle Scholar
  114. Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J, Plotz G, Jiricny J, Marra G (2002) Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology 122:211–219PubMedGoogle Scholar
  115. Tsurimoto T (1999) PCNA binding proteins. Front Biosci 4:D849–D858PubMedGoogle Scholar
  116. Umar A, Boland CR, Terdiman JP, Syngal S, De La Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedCrossRefGoogle Scholar
  117. Umar A, Buermeyer AB, Simon JA, Thomas DC, Clark AB, Liskay RM, Kunkel TA (1996) Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87:65–73PubMedGoogle Scholar
  118. Umar A, Risinger JI, Glaab WE, Tindall KR, Barrett JC, Kunkel TA (1998) Functional overlap in mismatch repair by human MSH3 and MSH6. Genetics 148:1637–1646PubMedGoogle Scholar
  119. Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425PubMedGoogle Scholar
  120. Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456PubMedGoogle Scholar
  121. Wagner R Jr, Meselson M (1976) Repair tracts in mismatched DNA heteroduplexes. Proc Natl Acad Sci USA 73:4135–4139PubMedGoogle Scholar
  122. Wang H, Hays JB (2004) Signaling from DNA mispairs to mismatch-repair excision sites despite intervening blockades. EMBO J 23:2126–2133PubMedGoogle Scholar
  123. Wang H, Yang Y, Schofield MJ, Du C, Fridman Y, Lee SD, Larson ED, Drummond JT, Alani E, Hsieh P, Erie DA (2003) DNA bending and unbending by MutS govern mismatch recognition and specificity. Proc Natl Acad Sci USA 100:14822–14827PubMedGoogle Scholar
  124. Watson P, Lynch HT (1993) Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71:677–685PubMedGoogle Scholar
  125. Welsh KM, Lu AL, Clark S, Modrich P (1987) Isolation and characterization of the Escherichia coli mutH gene product. J Biol Chem 262:15624–15629PubMedGoogle Scholar
  126. Wijnen J, Van Der Klift H, Vasen H, Khan PM, Menko F, Tops C, Meijers Heijboer H, Lindhout D, Moller P, Fodde R (1998) MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 20:326–328PubMedGoogle Scholar
  127. Worthley DL, Walsh MD, Barker M, Ruszkiewicz A, Bennett G, Phillips K, Suthers G (2005) Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128:1431–1436PubMedGoogle Scholar
  128. Wu Y, Berends MJ, Post JG, Mensink RG, Verlind E, Van Der Sluis T, Kempinga C, Sijmons RH, Van Der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM (2001) Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. Gastroenterology 120:1580–1587PubMedGoogle Scholar
  129. Yamamoto A, Schofield MJ, Biswas I, Hsieh P (2000) Requirement for Phe36 for DNA binding and mismatch repair by Escherichia coli MutS protein. Nucleic Acids Res 28:3564–3569PubMedGoogle Scholar
  130. Yan H, Papadopoulos N, Marra G, Perrera C, Jiricny J, Boland CR, Lynch HT, Chadwick RB, De La CA, Berg K, Eshleman JR, Yuan W, Markowitz S, Laken SJ, Lengauer C, Kinzler KW, Vogelstein B (2000) Conversion of diploidy to haploidy. Nature 403:723–724PubMedGoogle Scholar
  131. Zhang Y, Yuan F, Presnell SR, Tian K, Gao Y, Tomkinson AE, Gu L, Li GM (2005) Reconstitution of 5’-directed human mismatch repair in a purified system. Cell 122:693–705PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Klinik für Innere Medizin IIUniversitätsklinikum des SaarlandesHomburgGermany

Personalised recommendations