Monitoring the 5’UTR landscape reveals 5’terminal oligopyrimidine (TOP) motif switches to drive translational efficiencies

Abstract Transcriptional and translational control are key determinants of gene expression, however, to what extent these two processes can be collectively coordinated is still poorly understood. Here we use long-read sequencing to document the 5’and 3’untranslated region (UTR) isoform landscape of epidermal stem cells, wild-type keratinocytes and squamous cell carcinomas. Focusing on squamous cell carcinomas, we show that a small cohort of genes with alternative 5’UTR isoforms exhibit overall increased translational efficiencies and are enriched in ribosomal proteins and splicing factors. These 5’UTR isoforms with identical coding sequences either include or exclude 5’terminal oligopyrimidine (TOP) motifs and result in vastly altered translational efficiencies of the mRNA. Our findings suggest that switching between TOP and non-TOP motif-containing 5’UTR isoforms is an elegant and simple way to alter protein synthesis rates, set their sensitivity to the mTORC1-dependent nutrient-sensing pathway and direct the translational potential of an mRNA by the precise 5’UTR sequence.