tRNA modifications tune m6A-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 N⁶-methyladenosine (m⁶A) is read by tRNAs during translation. Codons that are modified with m⁶A 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 (mcm⁵s²U) 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 m⁶A and mcm⁵s²U biogenesis pathways-marked by a shift toward more mcm⁵s²U-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.