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Translation includes initiation, elongation, and termination, followed by ribosome recycling. We characterize a new sequence element in 5' untranslated regions that consists of an adjacent start and stop codon and thereby excludes elongation. In these start-stop elements, an initiating ribosome is simultaneously positioned for termination without having translocated. At the example of activating transcription factor 4 (ATF4), we demonstrate that start-stops modify downstream re-initiation, thereby repressing translation of upstream open reading frames and enhancing ATF4 inducibility under stress. Start-stop elements are abundant in both mammals and yeast and affect key regulators such as DROSHA and the oncogenic transcription factor NFIA. They provide a unique regulatory layer that impedes ribosome scanning without the energy-expensive peptide production that accompanies upstream open reading frames.

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