tRNA modifications tune m(6)A-dependent mRNA decay.

Chemically modified nucleotides in mRNA are critical regulators of gene expression, primarily through interactions with reader proteins that bind to these modifications. Here, we present a mechanism by which the epitranscriptomic mark N(6)-methyladenosine (m(6)A) is read by tRNAs during translation. Codons that are modified with m(6)A are decoded inefficiently by the ribosome, rendering them "non-optimal" and inducing ribosome collisions on cellular transcripts. This couples mRNA translation to decay. 5-Methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U) in the tRNA anticodon loop counteracts this effect. This unanticipated link between the mRNA and tRNA epitranscriptomes enables the coordinated decay of mRNA regulons, including those encoding oncogenic signaling pathways. In cancer, dysregulation of the m(6)A and mcm(5)s(2)U biogenesis pathways-marked by a shift toward more mcm(5)s(2)U-is associated with more aggressive tumors and poor prognosis. Overall, this pan-epitranscriptomic interaction represents a novel mechanism of post-transcriptional gene regulation with implications for human health.