m6A is decoded by modified tRNAs to coordinate mRNA decay [SLAM-Seq]

Chemically modified mRNA nucleotides are emerging as key regulators of gene expression. Their effects are typically thought to be mediated through reader proteins that selectively bind to RNA molecules containing these modifications. Here, we present a new mechanism by which N6 methyladenosine (m6A) couples the translation of messenger RNA (mRNA) to its decay. m6A-modified codons are decoded inefficiently by the ribosome, rendering them “non-optimal”. At these codons, m6A slows down elongating ribosomes and thereby triggers translation-dependent decay of the mRNA. Inefficient decoding of m6A-modified codons is counteracted by the transfer RNA (tRNA) anticodon modification 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U). mcm5s2U increases the decoding efficiency of a subset of m6A codons and thereby alleviates m6A-mediated mRNA decay. This unanticipated link between the mRNA and tRNA epitranscriptomes controls the decay of mRNAs of important oncogenic signaling pathways. The biogenesis of m6A and mcm5s2U is coordinated in normal tissues but dysregulated in cancer, where a shift towards more mcm5s2U stabilizes these RNAs and is associated with higher tumor aggressiveness and poor prognosis. Thus, the balance between m6A and mcm5s2U acts as a pan-epitranscriptomic mechanism that regulates gene expression and curtails tumorigenesis.