Research Focus
Two substrates are better than one: dual specificities for Dnmt2 methyltransferases

https://doi.org/10.1016/j.tibs.2006.04.005Get rights and content

Dnmt2 enzymes have been widely conserved during evolution and contain all of the signature motifs of DNA (cytosine-5)-methyltransferases; however, the DNA methyltransferase activity of these proteins is comparatively weak and their biochemical and functional properties remain enigmatic. Recent evidence now shows that Dnmt2 has a novel tRNA methyltransferase activity, raising the possibility that the biological roles of these proteins might be broader than previously thought. This finding has important implications for understanding the evolutionary relationships among these enzymes.

Section snippets

Eukaryotic DNA methyltransferases

DNA methylation is important in organismal development and human disease 1, 2. In eukaryotes, there are three distinct families of DNA methyltransferases: Dnmt1, Dnmt2 and Dnmt3 [3]. Whereas Dnmt3 enzymes seem to be responsible for establishing DNA methylation patterns (de novo methyltransferases), Dnmt1 enzymes are involved in maintaining methylation patterns. By contrast, the biochemical activity and the biological function of Dnmt2 enzymes have remained enigmatic for a long time.

Dnmt2

Dnmt2 methylates tRNAAsp

In a recent biochemical study, Goll et al. [11] generated Dnmt2 knockouts in diverse model systems (mouse, Drosophila and Arabidopsis) to investigate the function of this enzyme. Using RNA preparations from these Dnmt2 mutants, they found that tRNAAsp is methylated with high efficiency by Dnmt2. Intriguingly, this modification seems to be highly specific, because they did not detect Dnmt2-dependent methylation of other RNA molecules. Detailed mass spectrometric analyses indicated that the

Functional characterization of Dnmt2 enzymes

Drosophila and Dictyostelium are especially well suited to functional studies because both organisms contain a single Dnmt2-like methyltransferase candidate gene; thus, their use avoids the need to differentiate experimentally among related enzymatic activities with potentially overlapping functions. In both organisms, the gene encoding Dnmt2 is differentially expressed during development, suggesting that it might have a regulatory function. The mutation or knockout of Dnmt2 in either organism

Evolution of eukaryotic DNA methyltransferases

On the basis of the tRNAAsp methyltransferase activity of Dnmt2, Goll et al. [11] have suggested that eukaryotic DNA methylation might have evolved from eukaryotic RNA methylation. This proposal contrasts with the prevailing concept that eukaryotic DNA methylation evolved from prokaryotic restriction modification systems [13] and will have to be validated in the future by phylogenetic analyses. In the absence of any data supporting this idea, it should be noted that a dual – DNA and RNA

Acknowledgements

We acknowledge financial support from the Deutsche Forschungsgemeinschaft (Priority Programme Epigenetics).

References (25)

  • A. Dong

    Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant-resistant binding to DNA

    Nucleic Acids Res.

    (2001)
  • N. Kunert

    A Dnmt2-like protein mediates DNA methylation in Drosophila

    Development

    (2003)
  • Cited by (95)

    • Depletion of TRDMT1 affects 5-methylcytosine modification of mRNA and inhibits HEK293 cell proliferation and migration

      2019, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      This gene was originally defined as an enigmatic DNA methyltransferase named DNMT2 [1,17,18]. The original definition proved incorrect when Goll combined genetic and biochemical approaches and revealed that human DNMT2 actually did not methylate DNA but instead methylated a small RNA, specifically an aspartic acid tRNA (tRNAAsp) [3,19,20]. Understanding was still limited regarding tRNA modification until Squires found that NSUN2-mediated m5C was ubiquitous among coding and noncoding RNA and played an extremely important role in structural and metabolic stability [21].

    • Epigenetics and Genetics of Development

      2018, The Neurobiology of Brain and Behavioral Development
    • Influence of maternal obesity, diet and exercise on epigenetic regulation of adipocytes

      2017, Molecular Aspects of Medicine
      Citation Excerpt :

      However, recent evidence suggests that DNMT1, 3a and 3b might share roles, and are not distinct in their mechanisms of action (Jeltsch and Jurkowska, 2014). DNMT2, initially classed as a DNA methyltransferase, was discovered to be a tRNA methyltransferase (Goll et al., 2006; Jeltsch et al., 2006; Rai et al., 2007; Jurkowski et al., 2008), primarily serving to methylate RNA. DNMT3L, which has an important role in early development, is not thought to function as a DNA methyltransferase, but instead helps stimulate de novo methylation by DNMT3A, and for the establishment of maternal genomic imprints (Jeltsch et al., 2006; Uysal et al., 2015).

    • History and Modern View on DNA Modifications in the Brain

      2017, DNA Modifications in the Brain: Neuroepigenetic Regulation of Gene Expression
    View all citing articles on Scopus
    View full text