Reportedly, DNMT2/TRDMT1 mainly methylates tRNAs at C38 and prevents them from the cleavage under stress. It also plays an essential role in the survival and physiological homeostasis of organisms. Nevertheless, DNMT2/TRDMT1 exhibits much weaker tRNA methylation activity in vitro than other tRNA methyltransferases, TrmD and Trm5. Here, we explored the restricted tRNA methylation mechanism by DNMT2/TRDMT1. In the current study, the optimized buffer C at 37 °C was the best condition for DNMT2/TRDMT1 activation. Of note, Dithiothreitol (DTT) was an indispensable component for this enzyme catalysis. Moreover, reductants took similar effects on the conformation change and oligomeric formation of DNMT2/TRDMT1. Ultimately, LC-MS/MS result revealed that C292-C292 and C292-C287 were predominant intermolecular disulfide bonds in recombinant DNMT2/TRDMT1. Notably, DNMT2/TRDMT1 existed primarily as dimers via intermolecular disulfide bonds C79-C24, C292-C292, and C222-C24 in HEK293T cells. GSSG stress enhanced tRNA methylation level in the early stage of stress, whereas the DNMT2/TRDMT1 activity might be unfavorable along with this enzyme accumulation in the nucleus. Excitingly, GSH stress downregulated the DNMT2/TRDMT1 expression and promoted tRNA methylation in cells, probably through breaking intermolecular disulfide bonds in this enzyme. Thus, our findings demonstrated restricted tRNA methylation by disulfide bonds in DNMT2/TRDMT1, and will provide important implications for redox stress related-diseases.
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