Chromosoma

, Volume 119, Issue 1, pp 35–40 | Cite as

Solving the Dnmt2 enigma

Mini-Review

Abstract

Dnmt2 is a member of the animal DNA methyltransferase family of enzymes. While the role of other Dnmt proteins has been extensively characterized, comparably little is known about Dnmt2. This is surprising because Dnmt2 is the most widely conserved Dnmt protein, with homologues in protists, plants, fungi, and animals. In this review, we discuss the evidence supporting the seemingly contradictory roles of Dnmt2 in both DNA and RNA methylation. New studies are uncovering the enzymatic mechanisms that mediate these activities and also provide first insights into the biological functions of Dnmt2. Lastly, we also discuss observations that suggest a possible role for Dnmt2 in human health and disease, which further emphasizes the importance of defining Dnmt2-modulated cellular pathways in future studies.

References

  1. Alexandrov A, Chernyakov I, Gu W, Hiley SL, Hughes TR, Grayhack EJ, Phizicky EM (2006) Rapid tRNA decay can result from lack of nonessential modifications. Mol Cell 21:87–96CrossRefPubMedGoogle Scholar
  2. Bachman KE, Rountree MR, Baylin SB (2001) Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J Biol Chem 276:32282–32287CrossRefPubMedGoogle Scholar
  3. Banerjee S, Fisher O, Lohia A, Ankri S (2005) Entamoeba histolytica DNA methyltransferase (Ehmeth) is a nuclear matrix protein that binds EhMRS2, a DNA that includes a scaffold/matrix attachment region (S/MAR). Mol Biochem Parasitol 139:91–97CrossRefPubMedGoogle Scholar
  4. 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 29:439–448CrossRefPubMedGoogle Scholar
  5. Easwaran HP, Schermelleh L, Leonhardt H, Cardoso MC (2004) Replication-independent chromatin loading of Dnmt1 during G2 and M phases. EMBO Rep 5:1181–1186CrossRefPubMedGoogle Scholar
  6. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159CrossRefPubMedGoogle Scholar
  7. Fisher O, Siman-Tov R, Ankri S (2004) Characterization of cytosine methylated regions and 5-cytosine DNA methyltransferase (Ehmeth) in the protozoan parasite Entamoeba histolytica. Nucleic Acids Res 32:287–297CrossRefPubMedGoogle Scholar
  8. Fisher O, Siman-Tov R, Ankri S (2006) Pleiotropic phenotype in Entamoeba histolytica overexpressing DNA methyltransferase (Ehmeth). Mol Biochem Parasitol 147:48–54CrossRefPubMedGoogle Scholar
  9. Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514CrossRefPubMedGoogle Scholar
  10. 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 311:395–398CrossRefPubMedGoogle Scholar
  11. Gutierrez A, Sommer RJ (2004) Evolution of dnmt-2 and mbd-2-like genes in the free-living nematodes Pristionchus pacificus, Caenorhabditis elegans and Caenorhabditis briggsae. Nucleic Acids Res 32:6388–6396CrossRefPubMedGoogle Scholar
  12. Helm M (2006) Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res 34:721–733CrossRefPubMedGoogle Scholar
  13. Hengesbach M, Meusburger M, Lyko F, Helm M (2008) Use of DNAzymes for site-specific analysis of ribonucleotide modifications. RNA 14:180–187CrossRefPubMedGoogle Scholar
  14. Hermann A, Schmitt S, Jeltsch A (2003) The human Dnmt2 has residual DNA-(cytosine-C5) methyltransferase activity. J Biol Chem 278:31717–31721CrossRefPubMedGoogle Scholar
  15. Hopper AK, Phizicky EM (2003) tRNA transfers to the limelight. Genes Dev 17:162–180CrossRefPubMedGoogle Scholar
  16. Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM, Chaillet JR (2001) Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104:829–838CrossRefPubMedGoogle Scholar
  17. Inano K, Suetake I, Ueda T, Miyake Y, Nakamura M, Okada M, Tajima S (2000) Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem 128:315–321PubMedGoogle Scholar
  18. Jeltsch A, Nellen W, Lyko F (2006) Two substrates are better than one: dual specificities for Dnmt2 methyltransferases. Trends Biochem Sci 31:306–308CrossRefPubMedGoogle Scholar
  19. Jurkowski TP, Meusburger M, Phalke S, Helm M, Nellen W, Reuter G, Jeltsch A (2008) Human DNMT2 methylates tRNAAsp molecules using a DNA methyltransferase-like catalytic mechanism. RNA 14:1663–1670CrossRefPubMedGoogle Scholar
  20. Katoh M, Curk T, Xu Q, Zupan B, Kuspa A, Shaulsky G (2006) Developmentally regulated DNA methylation in Dictyostelium discoideum. Eukaryot Cell 5:18–25CrossRefPubMedGoogle Scholar
  21. Kuhlmann M, Borisova BE, Kaller M, Larsson P, Stach D, Na J, Eichinger L, Lyko F, Ambros V, Soderbom F, Hammann C, Nellen W (2005) Silencing of retrotransposons in Dictyostelium by DNA methylation and RNAi. Nucleic Acids Res 33:6405–6417CrossRefPubMedGoogle Scholar
  22. Kunert N, Marhold J, Stanke J, Stach D, Lyko F (2003) A Dnmt2-like protein mediates DNA methylation in Drosophila. Development 130:5083–5090CrossRefPubMedGoogle Scholar
  23. Lin MJ, Tang LY, Reddy MN, Shen CK (2005) DNA methyltransferase gene dDnmt2 and longevity of Drosophila. J Biol Chem 280:861–864CrossRefPubMedGoogle Scholar
  24. Lyko F, Ramsahoye BH, Jaenisch R (2000) DNA methylation in Drosophila melanogaster. Nature 408:538–540CrossRefPubMedGoogle Scholar
  25. Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM, Bestor TH (1998) Sex-specific exons control DNA methyltransferase in mammalian germ cells. Development 125:889–897PubMedGoogle Scholar
  26. Okano M, Xie S, Li E (1998) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19:219–220CrossRefPubMedGoogle Scholar
  27. Phalke S, Nickel O, Walluscheck D, Hortig F, Reuter G (2009) Epigenetic control of retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine 5 methyltransferase DNMT2. Nat Genet 41:696–702CrossRefPubMedGoogle Scholar
  28. Pinarbasi E, Elliott J, Hornby DP (1996) Activation of a yeast pseudo DNA methyltransferase by deletion of a single amino acid. J Mol Biol 257:804–813CrossRefPubMedGoogle Scholar
  29. Rai K, Chidester S, Zavala CV, Manos EJ, James SR, Karpf AR, Jones DA, Cairns BR (2007) Dnmt2 functions in the cytoplasm to promote liver, brain, and retina development in zebrafish. Genes Dev 21:261–266CrossRefPubMedGoogle Scholar
  30. Sakaguchi A, Karachentsev D, Seth-Pasricha M, Druzhinina M, Steward R (2008) Functional characterization of the Drosophila Hmt4–20/Suv4–20 histone methyltransferase. Genetics 179:317–322CrossRefPubMedGoogle Scholar
  31. Schaefer M, Hagemann S, Hanna K, Lyko F (2009a) Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res:in pressGoogle Scholar
  32. Schaefer M, Pollex T, Hanna K, Lyko F (2009b) RNA cytosine methylation analysis by bisulfite sequencing. Nucleic Acids Res 37:e12CrossRefPubMedGoogle Scholar
  33. Schaefer M, Steringer JP, Lyko F (2008) The Drosophila cytosine-5 methyltransferase Dnmt2 is associated with the nuclear matrix and can access DNA during mitosis. PLoS ONE 3:e1414CrossRefPubMedGoogle Scholar
  34. Sprinzl M, Vassilenko KS (2005) Compilation of tRNA sequences and sequences of tRNA genes. Nucleic Acids Res 33:D139–140CrossRefPubMedGoogle Scholar
  35. Wilkinson CR, Bartlett R, Nurse P, Bird AP (1995) The fission yeast gene pmt1+ encodes a DNA methyltransferase homologue. Nucleic Acids Res 23:203–210CrossRefPubMedGoogle Scholar
  36. Yoder JA, Bestor TH (1998) A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum Mol Genet 7:279–284CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Division of EpigeneticsGerman Cancer Research CenterHeidelbergGermany
  2. 2.Deutsches KrebsforschungszentrumHeidelbergGermany

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