Comprehensive translational profiling and STE AI uncover rapid control of protein biosynthesis during cell stress

Translational control is important in all life, but it remains a challenge to accurately quantify. When ribosomes translate messenger (m)RNA into proteins, they attach to the mRNA in series, forming poly(ribo)somes, and can co-localize. Here, we computationally model new types of co-localized riboso...

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Published inNucleic acids research Vol. 52; no. 13; pp. 7925 - 7946
Main Authors Horvath, Attila, Janapala, Yoshika, Woodward, Katrina, Mahmud, Shafi, Cleynen, Alice, Gardiner, Elizabeth E, Hannan, Ross D, Eyras, Eduardo, Preiss, Thomas, Shirokikh, Nikolay E
Format Journal Article
LanguageEnglish
Published England Oxford University Press 22.07.2024
Subjects
Biochemistry, Molecular Biology
Genomics
Life Sciences
Quantitative Methods
RNA and RNA-protein complexes
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Summary:Translational control is important in all life, but it remains a challenge to accurately quantify. When ribosomes translate messenger (m)RNA into proteins, they attach to the mRNA in series, forming poly(ribo)somes, and can co-localize. Here, we computationally model new types of co-localized ribosomal complexes on mRNA and identify them using enhanced translation complex profile sequencing (eTCP-seq) based on rapid in vivo crosslinking. We detect long disome footprints outside regions of non-random elongation stalls and show these are linked to translation initiation and protein biosynthesis rates. We subject footprints of disomes and other translation complexes to artificial intelligence (AI) analysis and construct a new, accurate and self-normalized measure of translation, termed stochastic translation efficiency (STE). We then apply STE to investigate rapid changes to mRNA translation in yeast undergoing glucose depletion. Importantly, we show that, well beyond tagging elongation stalls, footprints of co-localized ribosomes provide rich insight into translational mechanisms, polysome dynamics and topology. STE AI ranks cellular mRNAs by absolute translation rates under given conditions, can assist in identifying its control elements and will facilitate the development of next-generation synthetic biology designs and mRNA-based therapeutics. Graphical Abstract Graphical Abstract
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The first two authors should be regarded as Joint First Authors.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkae365