GSE173971
m6A is decoded by modified tRNAs to coordinate mRNA decay [ribosome profiling]
In eukaryotes, the genetic code is transcribed into messenger RNA (mRNA) in the nucleus and decoded by transfer RNA (tRNA) in the cytosol.  Nuclear mRNA processing events that do not affect the nucleotide sequence of an mRNA are thought to be invisible to tRNAs during protein translation in the cytosol.  Here, we report a mechanism by which the modified mRNA nucleotide N6-methyladenosine (m6A) connects nuclear mRNA processing to tRNA decoding. m6A is deposited in the protein coding sequence (CDS) of mRNAs with long exons, where it slows the decoding of a subset of m6A-modified codons in vivo.  Translation of codons with m6A at the wobble position is facilitated by 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U), a modified nucleotide of the tRNA anticodon loop that juxtaposes the wobble-m6A.  This unanticipated link between the mRNA and tRNA epitranscriptomes controls mRNA half-life in a translation-dependent manner and connects the exon-intron architecture of mRNAs to their turnover.  The pathways for m6A and mcm5s2U biogenesis are tightly co-regulated in human tissues but deregulated in cancer cells. In breast cancer, a shift towards more mcm5s2U is associated with tumor aggressiveness and poor prognosis.  Thus, the m6A/mcm5s2U-balance has evolved as a pan-epitranscriptomic mechanism that coordinates gene expression changes and curtails tumorigenesis. Overall design: Ribosome profiling analysis of the wobble uridine (U34) modification enzymes knockouts