tRNA (cytosine(38)-C(5))-methyltransferase (DNMT2)

tRNA (cytosine(38)-C(5))-methyltransferase, commonly known as DNMT2 or TRDMT1, is a unique member of the methyltransferase family that primarily targets RNA rather than DNA [1, 3]. It specifically catalyzes the 5-methylcytosine (m5C) modification at position 38 in the anticodon loop of tRNA-Asp, tRNA-Val, and tRNA-Gly [8, 10]. This modification is essential for tRNA stability, as it protects these molecules from endonucleolytic cleavage into tRNA fragments during cellular stress [16]. Beyond its role in RNA metabolism, DNMT2 is involved in the cellular stress response, DNA damage repair, and the regulation of protein synthesis [5, 6]. In clinical contexts, DNMT2 is overexpressed in several malignancies, including hepatocellular carcinoma and osteosarcoma, where it promotes tumor progression and resistance to therapies such as Bortezomib [4, 5]. It also plays a role in the maintenance of genome integrity and the modulation of cellular senescence [6]. While traditional DNA methyltransferase inhibitors like Azacitidine can affect its activity through off-target mechanisms, DNMT2 is increasingly recognized as a distinct therapeutic target for modulating the epitranscriptome [1, 2]. Targeting DNMT2 may provide new strategies for treating refractory cancers and certain viral or parasitic infections [1].

Other names

TRDMT1tRNA aspartic acid methyltransferase 1DNA (cytosine-5)-methyltransferase-like protein 2Pmt1DnmAEhmet

DNMT2 catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the C5 position of cytosine 38 in the anticodon loop of specific tRNAs (tRNA-Asp, tRNA-Val, tRNA-Gly) to form 5-methylcytosine (m5C), utilizing a catalytic mechanism similar to DNA methyltransferases [3, 8, 10].