Regulatory start-stop elements in 5' untranslated regions pervasively modulate translation

Abstract

Sequence elements within the 5 untranslated region (UTR) of eukaryotic genes, e.g. upstream open reading frames (uORFs), control translation of eukaryotic genes. We describe an element consisting of a start codon immediately followed by a stop codon which is distinct from uORFs in the lack of an elongation step. Start-stops have been described for specific cases, but their widespread impact has been overlooked. Start-stop elements occur in the 5UTR of 1, 417 human genes and are more often occupied with a ribosome than canonical uORFs or control sequences. Start-stops efficiently halt ribosomes without evidence for accelerated RNA turnover, therefore acting as a barrier for the scanning of the small ribosomal subunit and repressing downstream translation. Our results suggest a model by which the ribosome undergoes repeated cycles of termination and partial ribosomal recycling, during which the large subunit detaches, but the 40S subunit with the Met-tRNAiMet remains associated with the mRNA to be rejoined by the 60S subunit. Start-stop elements occur in many transcription factors and signaling genes, and affect cellular fate via different routes. We investigate the start-stop element in several genes, i.e. MORF4L1, SLC39A1, and PSPC1, and in more detail in ATF4.