Mechanism and biological role of Dnmt2 in Nucleic Acid Methylation

Abstract

A group of homologous nucleic acid modification enzymes called Dnmt2, Trdmt1, Pmt1, DnmA, and Ehmet in different model organisms catalyze the transfer of a methyl group from the cofactor S-adenosyl-methionine (SAM) to the carbon-5 of cytosine residues. Originally considered as DNA MTases, these enzymes were shown to be tRNA methyltransferases about a decade ago. Between the presumed involvement in DNA modification-related epigenetics, and the recent foray into the RNA modification field, significant progress has characterized Dnmt2-related research. Here, we review this progress in its diverse facets including molecular evolution, structural biology, biochemistry, chemical biology, cell biology and epigenetics.

Keywords: DNA methylation; RNA methylation; epigenetics; methylcytidine; tRNA.

Figure 1.

Consensus model of the phylogeny of DNA 5mC / RNA m⁵C methyltransferases. Dnmt1 and Dnmt2/Dnmt3 enzymes have independent origin in the prokaryotic DNA methyltransferases. The putative precursor of the Dnmt2 family changed its substrate preference from DNA to RNA (indicated with *). Green shading denotes DNA methyltransferases, pink denotes RNA methyltransferases.

Figure 2.

Structure of Entamoeba histolytica methyltransferase EhMeth (3QV2) and structure of tRNA^Asp from S. cerevisiae (1VTQ) drawn in same scale. Dnmt2 is shown in schematic drawing in orange with SAM in yellow.

Figure 3.

Substrate spectrum of Dnmt2. Dnmt2 has been shown to methylate tRNA-Asp and depending on the species tRNA^Gly, tRNA^Val, and tRNA^Glu. Whether other tRNAs, RNAs or DNA are methylated by this enzyme is an open question.

Figure 4.

Different views of DNMT2 in surface representation. The residues subjected to mutagenesis are colored according to their residual activity. The cofactor product S-adenosyl-l-homocysteine is colored blue. Panel A shows that residues which strongly interfere with catalysis (colored red here) cluster on the “front” face of the enzyme and surround a cleft that also contains the SAM binding pocket and the catalytic residues. Panel B represents a view of the “back side” of the enzyme after a 180° rotation of the view shown in panel A about the vertical axis. Reproduced from with permission. Copyright (2012) American Chemical Society.

Figure 5.

(A) Function of Dnmt2. Methylation of tRNA^Asp_GUC enhances its charging by AspRS. This stimulates the translation of Asp-rich proteins. (B) Function of Dnmt2. Methylation of tRNAs protects them from cleavage into tRNA fragments and increases overall translation. Massive production of tRNA fragments after loss or downregulation of Dnmt2 affects Dicer dependent processing of small RNAs. C) Function of Dnmt2. Depending on nutrition or other signals, Queuosine is incorporated into tRNA^Asp_GUC at position 34. This stimulates Dnmt2 mediated methylation and triggers downstream effects.