Translation initiation downstream from annotated start codons in human mRNAs coevolves with the Kozak context

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dc.contributor.authorBenitez-Cantos, Maria S.
dc.contributor.authorYordanova, Martina M.
dc.contributor.authorO'Connor, Patrick B. F.
dc.contributor.authorZhdanov, Alexander V.
dc.contributor.authorKovalchuk, Sergey I.
dc.contributor.authorPapkovsky, Dmitri B.
dc.contributor.authorAndreev, Dmitry E.
dc.contributor.authorBaranov, Pavel V.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderHealth Research Boarden
dc.contributor.funderWellcome Trusten
dc.contributor.funderRussian Science Foundationen
dc.contributor.funderUniversidad de Granadaen
dc.contributor.funderEuropean Regional Development Funden
dc.contributor.funderIrish Research Councilen
dc.date.accessioned2022-07-05T14:56:02Z
dc.date.available2022-07-05T14:56:02Z
dc.date.issued2020-07
dc.date.updated2022-07-05T14:16:00Z
dc.description.abstractEukaryotic translation initiation involves preinitiation ribosomal complex 5'-to-3' directional probing of mRNA for codons suitable for starting protein synthesis. The recognition of codons as starts depends on the codon identity and on its immediate nucleotide context known as Kozak context. When the context is weak (i.e., nonoptimal), leaky scanning takes place during which a fraction of ribosomes continues the mRNA probing. We explored the relationship between the context of AUG codons annotated as starts of protein-coding sequences and the next AUG codon occurrence. We found that AUG codons downstream from weak starts occur in the same frame more frequently than downstream from strong starts. We suggest that evolutionary selection on in-frame AUGs downstream from weak start codons is driven by the advantage of the reduction of wasteful out-of-frame product synthesis and also by the advantage of producing multiple proteoforms from certain mRNAs. We confirmed translation initiation downstream from weak start codons using ribosome profiling data. We also tested translation of alternative start codons in 10 specific human genes using reporter constructs. In all tested cases, initiation at downstream start codons was more productive than at the annotated ones. In most cases, optimization of Kozak context did not completely abolish downstream initiation, and in the specific example of CMPK1 mRNA, the optimized start remained unproductive. Collectively, our work reveals previously uncharacterized forces shaping the evolution of protein-coding genes and points to the plurality of translation initiation and the existence of sequence features influencing start codon selection, other than Kozak context.en
dc.description.sponsorshipUniversidad de Granada (Plan Propio de Investigación 2019)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBenitez-Cantos, M. S., Yordanova, M. M., O'Connor, P. B. F., Zhdanov, A. V., Kovalchuk, S. I., Papkovsky, D. B., Andreev, D. E. and Baranov, P. V. (2020) 'Translation initiation downstream from annotated start codons in human mRNAs coevolves with the Kozak context', Genome Research, 30 (7), pp. 974-984. doi: 10.1101/gr.257352.119en
dc.identifier.doi10.1101/gr.257352.119en
dc.identifier.endpage984en
dc.identifier.issn1549-5469
dc.identifier.issued7en
dc.identifier.journaltitleGenome Researchen
dc.identifier.startpage974en
dc.identifier.urihttps://hdl.handle.net/10468/13340
dc.identifier.volume30en
dc.language.isoenen
dc.publisherCold Spring Harbor Lab Pressen
dc.relation.projectinfo:eu-repo/grantAgreement/WT/Molecular Basis of Cell Function/210692//Molecular memory in human AMD1 gene: mechanisms and functions./en
dc.relation.projectinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF/00121/2012/CP0172/CT0004/PT/MG-square: containing the growth of osteosarcoma MG63 cells with metallopharmaceuticals/IF/00121/2012/CP0172/CT0004en
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2276/IE/I-PIC Irish Photonic Integration Research Centre/en
dc.rights© 2020 Benitez-Cantos et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectGeneticsen
dc.subjectProtein synthesisen
dc.titleTranslation initiation downstream from annotated start codons in human mRNAs coevolves with the Kozak contexten
dc.typeArticle (peer-reviewed)en
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