Mammalian DNA methyltransferases
Languages of publication
DNA methylation is an epigenetic process affecting gene expression and chromatin organization. It can heritably silence or activate transcription of genes without any change in their nucleotide sequences, and for a long time was not recognized as an important regulatory mechanism. However, during the recent years it has been shown that improper methylation, especially hypermethylation of promoter regions, is observed in nearly all steps of tumorigenesis. Aberrant methylation is also the cause of several major pathologies including developmental disorders involving chromosome instabilities and mental retardation. A great progress has been made in our understanding of the enzymatic machinery involved in establishing and maintaining methylation patterns. This allowed for the development of new diagnostic tools and epigenetic treatment therapies. The new approaches hold a great potential; several inhibitors of DNA methyltransferases have already shown very promising therapeutic effects.
- Aapola U, Kawasaki K, Scott HS, Ollila J, Vihinen M, Heino M, Shintani A, Kawasaki K, Minoshima S, Krohn K, Antonarakis SE, Shimizu N, Kudoh J, Peterson P (2000) Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65: 293-298.
- Araujo FD, Croteau S, Slack AD, Milutinovic S, Bigey P, Price GB, Zannis-Hajopoulos M, Szyf M (2001) The DNMT1 target recognition domain resides in the N terminus. J Biol Chem 276: 6930-6936.
- Bakin AV, Curran T (1999) Role of DNA 5-methylcytosine transferase in cell transformation by fos. Science 283: 387-390.
- Baniushin BF (2005) Methylation of adenine residues in DNA of eukaryotes. Mol Biol (Mosk) 39: 557-566 (in Russian).
- Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16: 168-174.
- Baylin S, Bestor TH (2002) Altered methylation patt erns in cancer cell genomes: cause or consequence? Cancer Cell 1: 299-305.
- Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9: 2395-2402.
- Bestor TH, Verdine GL (1994) DNA methyltransferases. Curr Opin Cell Biol 6: 380-389.
- Bestor T, Laudano A, Mattaliano R, Ingram V (1988) Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol 203: 971-983.
- Biniszkiewicz D, Gribnau J, Ramsahoye B, Gaudet F, Eggan K, Humpherys D, Mastrangelo MA, Jun Z, Walter J, Jaenisch R (2002) Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol 22: 2124-2135.
- Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16: 6-21.
- Bourc'his D, Xu GL, Lin CS, Bollman B, Bestor TH (2001) Dnmt3L and the establishment of maternal genomic imprints. Science 294: 2536-2539.
- Brueckner B, Boy RG, Siedlecki P, Musch T, Kliem HC, Zielenkiewicz P, Suhai S, Wiessler M, Lyko F (2005) Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res 65: 6305-6311.
- Callebaut I, Courvalin JC, Mornon JP (1999) The BAH (bromo-adjacent homology) domain: a link between DNA methylation, replication and transcriptional regulation. FEBS Lett 446: 189-193.
- Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395: 89-93.
- Chuang LS, Ng HH, Chia JN, Li BF (1996) Characterisation of independent DNA and multiple Zn-binding domains at the N terminus of human DNA-(cytosine-5) methyltransferase: modulating the property of a DNA-binding domain by contiguous Zn-binding motifs. J Mol Biol 257: 935-948.
- Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (1997) Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 277: 1996-2000.
- Cosma MP, Tanaka T, Nasmyth K (1999) Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter. Cell 97: 299-311.
- Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 25: 315-319.
- Dong A, Yoder JA, Zhang X, Zhou L, Bestor TH, Cheng X (2001) Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant-resistant binding to DNA. Nucleic Acids Res 29: 439-448.
- Eden A, Gaudet F, Waghmare A, Jaenisch R (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300: 455.
- Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21: 5400-5413.
- Esteller M (2005) Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol 45: 629-656.
- Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG (2000) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60: 2368-2371.
- Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61: 3225-3229.
- Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS (2003) Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 63: 7563-7570.
- Fatemi M, Hermann A, Pradhan S, Jeltsch A (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J Mol Biol 309: 1189-1199.
- Freitag M, Selker EU (2005) Controlling DNA methylation: many roads to one modification. Curr Opin Genet Dev 15: 191-199.
- Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74: 481-514.
- Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, Golic KG, Jacobsen SE, Bestor TH (2006) Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311: 395-398.
- Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch H, Wiesner G, Ferguson K, Eng C, Park JG, Kim SJ, Markowitz S (2000) Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet 26: 16-17.
- Gromova ES, Khoroshaev AV (2003) Prokaryotic DNA methyltransferases: the structure and the mechanism of interaction with DNA. Mol Biol (Mosk) 37: 300-314 (in Russian).
- Guo G, Wang W, Bradley A (2004) Mismatch repair genes identified using genetic screens in Blm-deficient embryonic stem cells. Nature 429: 891-895.
- Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB (1997) Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 57: 837-841.
- Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95: 6870-6875.
- Hermann A, Schmitt S, Jeltsch A (2003) The human Dnmt2 has residual DNA-(cytosine-C5) methyltransferase activity. J Biol Chem 278: 31717-31721.
- Hermann A, Gowher H, Jeltsch A (2004) Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci 61: 2571-2587.
- Hsieh CL (2005) The de novo methylation activity of Dnmt3a is distinctly different than that of Dnmt1. BMC Biochem 6: 6.
- Jackson-Grusby L, Laird PW, Magge SN, Moeller BJ, Jaenisch R (1997) Mutagenicity of 5-aza-2'-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc Natl Acad Sci USA 94: 4681-4685.
- Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21: 163-167.
- Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415-428.
- Juttermann R, Li E, Jaenisch R (1994) Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci USA 91: 11797-11801.
- Kim D, Lee IS, Jung JH, Lee CO, Choi SU (1999) Psammaplin A, a natural phenolic compound, has inhibitory effect on human topoisomerase II and is cytotoxic to cancer cells. Anticancer Res 19: 4085-4090.
- Kim JS, Han J, Shim YM, Park J, Kim DH (2005) Aberrant methylation of H-cadherin (CDH13) promoter is associated with tumor progression in primary nonsmall cell lung carcinoma. Cancer 104: 1825-1833.
- Klimasauskas S, Kumar S, Roberts RJ, Cheng X (1994) HhaI methyltransferase flips its target base out of the DNA helix. Cell 76: 357-369.
- Kunert N, Marhold J, Stanke J, Stach D, Lyko F (2003) A Dnmt2-like protein mediates DNA methylation in Drosophila. Development 130: 5083-5090.
- Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E, Weinberg RA, Jaenisch R (1995) Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81: 197-205.
- Lauster R, Trautner TA, Noyer-Weidner M (1989) Cytosine-specific type II DNA methyltransferases. A conserved enzyme core with variable target-recognizing domains. J Mol Biol 206: 305-312.
- Lei H, Oh SP, Okano M, Juttermann R, Goss KA, Jaenisch R, Li E (1996) De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122: 3195-3205.
- Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3: 662-673.
- Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69: 915-926.
- Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366: 362-365.
- Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, Laird PW, Jones PA (2002) Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 22: 480-491.
- Liu Y, Oakeley EJ, Sun L, Jost JP (1998) Multiple domains are involved in the targeting of the mouse DNA methyltransferase to the DNA replication foci. Nucleic Acids Res 26: 1038-1045.
- Lyko F, Brown R (2005) DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst 97: 1498-1506.
- Lyko F, Ramsahoye BH, Kashevsky H, Tudor M, Mastrangelo MA, Orr-Weaver TL, Jaenisch R (1999) Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila. Nat Genet 23: 363-366.
- Margot JB, Aguirre-Arteta AM, Di Giacco BV, Pradhan S, Roberts RJ, Cardoso MC, Leonhardt H (2000) Structure and function of the mouse DNA methyltransferase gene: Dnmt1 shows a tripartite structure. J Mol Biol 297: 293-300.
- Myohanen SK, Baylin SB, Herman JG (1998) Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. Cancer Res 58: 591-593.
- Okano M, Xie S, Li E (1998) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19: 219-220.
- Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247-257.
- Panning B, Jaenisch R (1996) DNA hypomethylation can activate Xist expression and silence X-linked genes. Genes Dev 10: 1991-2002.
- Pina IC, Gautschi JT, Wang GY, Sanders ML, Schmitz FJ, France D, Cornell-Kennon S, Sambucetti LC, Remiszewski SW, Perez LB, Bair KW, Crews P (2003) Psammaplins from the sponge Pseudoceratina purpurea: inhibition of both histone deacetylase and DNA methyltransferase. J Org Chem 68: 3866-3873.
- Posfai J, Bhagwat AS, Posfai G, Roberts RJ (1989) Predictive motifs derived from cytosine methyltransferases. Nucleic Acids Res 17: 2421-2435.
- Post WS, Goldschmidt-Clermont PJ, Wilhide CC, Heldman AW, Sussman MS, Ouyang P, Milliken EE, Issa JP (1999) Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc Res 43: 985-991.
- Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R (2000) Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci USA 97: 5237-5242.
- Reinisch KM, Chen L, Verdine GL, Lipscomb WN (1995) The crystal structure of HaeIII methyltransferase convalently complexed to DNA: an extrahelical cytosine and rearranged base pairing. Cell 82: 143-153.
- Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, Vogelstein B, Baylin SB, Schuebel KE (2000) CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404: 1003-1007.
- Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, Cui H, Feinberg AP, Lengauer C, Kinzler KW, Baylin SB, Vogelstein B (2002) DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416: 552-556.
- Rideout WM 3rd, Coetzee GA, Olumi AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249: 1288-1290.
- Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A, MacLeod AR (2003) DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 33: 61-65.
- Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6: 597-610.
- Robertson KD, Wolffe AP (2000) DNA methylation in health and disease. Nat Rev Genet 1: 11-19.
- Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP (2000) DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25: 338-342.
- Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25: 269-277.
- Santi DV, Garrett CE, Barr PJ (1983) On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs. Cell 33: 9-10.
- Siedlecki P, Boy RG, Comagic S, Schirrmacher R, Wiessler M, Zielenkiewicz P, Suhai S, Lyko F (2003) Establishment and functional validation of a structural homology model for human DNA methyltransferase 1. Biochem Biophys Res Commun 306: 558-563.
- Siedlecki P, Boy RG, Musch T, Brueckner B, Suhai S, Lyko F, Zielenkiewicz P (2006) Discovery of two novel, small-molecule inhibitors of DNA methylation. J Med Chem 49: 678-683.
- Singal R, Ginder GD (1999) DNA methylation. Blood 93: 4059-4070.
- Slater LM, Allen MD, Bycroft M (2003) Structural variation in PWWP domains. J Mol Biol 330: 571-576.
- Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW (2001) Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409: 207-211.
- Szyf M (2005) DNA methylation and demethylation as targets for anticancer therapy. Biochemistry (Mosc) 70: 533-549.
- Ushijima T (2005) Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer 5: 223-231.
- van‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530-536.
- Villar-Garea A, Fraga MF, Espada J, Esteller M (2003) Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res 63: 4984-4989.
- Wu J, Issa JP, Herman J, Bassett DE Jr, Nelkin BD, Baylin SB (1993) Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci USA 90: 8891-8895.
- Yoder JA, Bestor TH (1998) A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum Mol Genet 7: 279-284.
- Yoder JA, Soman NS, Verdine GL, Bestor TH (1997) DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J Mol Biol 270: 385-395.
- Yoon JH, Smith LE, Feng Z, Tang M, Lee CS, Pfeifer GP (2001) Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res 61: 7110-7117.
- Zimmermann C, Guhl E, Graessmann A (1997) Mouse DNA methyltransferase (MTase) deletion mutants that retain the catalytic domain display neither de novo nor maintenance methylation activity in vivo. Biol Chem 378: 393-405.
Publication order reference