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

Abstract Various mechanisms controlling ribosome scanning and initiation have been identified within the 5’ untranslated region (UTR) of eukaryotic genes, including upstream open reading frames, specific sequence motifs, and secondary structures. We describe the impact and distinct characteristics of a translation regulatory element consisting of a start codon immediately followed by a stop codon. While to date this start-stop element has been described only for specific cases, we identified them in the 5’UTR of hundreds of human genes whereby their general impact on translation control in mammalian cells has been unnoticed. We show that the element is evolutionarily conserved and represses translation of the downstream open reading frames. While having no apparent impact on translation termination or RNA stability, start-stops efficiently halt ribosomes and act as a barrier for the scanning of the small ribosomal subunit. Start-stop element occurs in many transcription factors and key signaling genes, and we highlight routes in which they can affect cellular fate. We investigate the start-stop element in several genes, i.e. MORF4L1 , IFNAR1 , SLC39A1 , and PSPC1 , and delineate the role of the start-stop in translation regulation of ATF4 mRNA. Thus, start-stops uniquely modulate translation through elongation-less ribosome stalling.