TET-mediated 5-methylcytosine oxidation in tRNA promotes translation

Oxidation of 5-methylcytosine (5mC) in DNA by the ten-eleven translocation (TET) family of enzymes is indispensable for gene regulation in mammals. More recently, evidence has emerged to support a biological function for TET-mediated m(5)C oxidation in messenger RNA. Here, we describe a previously uncharacterized role of TET-mediated m(5C) oxidation in transfer RNA (tRNA). We found that the TET-mediated oxidation product 5-hydroxylmethylcytosine (hm5C) is specifically enriched in tRNA inside cells and that the oxidation activity of TET2 on m(5)C in tRNAs can be readily observed in vitro. We further observed that hm(5)C levels in tRNA were significantly decreased in Tet(2) KO mouse embryonic stem cells (mESCs) in comparison with wild-type mESCs. Reciprocally, induced expression of the catalytic domain of TET2 led to an obvious increase in hm(5)C and a decrease in m(5)C in tRNAs relative to uninduced cells. Strikingly, we also show that TET2-mediated m(5)C oxidation in tRNA promotes translation in vitro. These results suggest TET2 may influence translation through impacting tRNA methylation and reveal an unexpected role for TET enzymes in regulating multiple nodes of the central dogma.

Automated summary

The oxidation of 5-methylcytosine in DNA by TET enzymes is crucial for gene regulation, and recent evidence suggests a biological function for TET-mediated m(5)C oxidation in both mRNA and tRNA. Specifically, TET2-mediated oxidation of m(5)C in tRNA promotes translation and influences tRNA methylation. These findings reveal an unexpected role for TET enzymes in regulating multiple aspects of the central dogma.