tRNA (cytosine-5)-methyltransferase (DNMT2) (DNMT2)

DNMT2 (tRNA (cytosine-5)-methyltransferase) is an evolutionarily conserved enzyme initially identified due to its sequence similarity to DNA methyltransferases. Despite its name and homology, DNMT2’s primary biological function in mammals and many eukaryotes is to methylate cytosine 38 on specific tRNAs (notably tRNA^Asp^, tRNA^Gly^, and tRNA^Val^) at the 5-position, contributing to tRNA stability and accuracy of protein synthesis rather than to DNA methylation[1][3][5][6]. Structurally, DNMT2 contains all canonical motifs of DNA-(cytosine 5)-methyltransferases and uses catalytic mechanisms akin to its DNA-methylating relatives, but biochemical studies have shown only extremely weak or absent DNA methylation activity in vivo. Functionally, DNMT2 is essential for protecting tRNA from endonuclease cleavage, thereby securing codon fidelity and correct translation, which is particularly important in stem cell differentiation and hematopoiesis[3]. DNMT2 has also been implicated in cellular stress responses and potentially in disease states where tRNA or translation regulation is disrupted. No direct pharmacological inhibitors or drugs targeting DNMT2 have been described to date.

Other names

Dnmt2Trdmt1DNA methyltransferase homolog 2tRNA aspartic acid methyltransferase 1TRDMT1tRNA methyltransferase DNMT2

Inhibitors would be expected to block cytosine-5 methylation of tRNA and alter translation fidelity As of now, no direct small-molecule drugs known to target DNMT2 specifically