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

Rendleman, J.; Mohammad, M. P.; Pressler, M.; Maity, S.; Hronova, V.; Gao, Z.; Herrmannova, A.; Lei, A.; Allgoewer, K.; Sultanov, D.; Hinckley, W. E.; Szkop, K.; Topisirovic, I.; Larsson, O.; Hatzoglou, M.; Valasek, L. S.; Vogel, C.

doi:10.1101/2021.07.26.453809

bioRxiv · 10.1101/2021.07.26.453809

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

Rendleman, J.·Mohammad, M. P.·Pressler, M.·Maity, S.·Hronova, V.·Gao, Z.·Herrmannova, A.·Lei, A.·Allgoewer, K.·Sultanov, D.·Hinckley, W. E.·Szkop, K.·Topisirovic, I.·Larsson, O.·Hatzoglou, M.·Valasek, L. S.·Vogel, C.

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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.

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Rendleman, J., Mohammad, M. P., Pressler, M., Maity, S., Hronova, V., Gao, Z., Herrmannova, A., Lei, A., Allgoewer, K., Sultanov, D., Hinckley, W. E., Szkop, K., Topisirovic, I., Larsson, O., Hatzoglou, M., Valasek, L. S., Vogel, C.. 2021-07-26. Regulatory start-stop elements in 5' untranslated regions pervasively modulate translation. https://doi.org/10.1101/2021.07.26.453809

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