TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response

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dc.contributor.authorAndreev, Dmitry E.
dc.contributor.authorArnold, Maxim
dc.contributor.authorKiniry, Stephen J.
dc.contributor.authorLoughran, Gary
dc.contributor.authorMichel, Audrey M.
dc.contributor.authorRachinskii, Dmitrii
dc.contributor.authorBaranov, Pavel V.
dc.contributor.funderIrish Research Council
dc.contributor.funderRussian Science Foundation
dc.contributor.funderNational Science Foundation
dc.contributor.funderScience Foundation Ireland
dc.date.accessioned2018-09-20T15:53:39Z
dc.date.available2018-09-20T15:53:39Z
dc.date.issued2018
dc.description.abstractTranslation initiation is the rate-limiting step of protein synthesis that is downregulated during the Integrated Stress Response (ISR). Previously, we demonstrated that most human mRNAs that are resistant to this inhibition possess translated upstream open reading frames (uORFs), and that in some cases a single uORF is sufficient for the resistance. Here we developed a computational model of Initiation Complexes Interference with Elongating Ribosomes (ICIER) to gain insight into the mechanism. We explored the relationship between the flux of scanning ribosomes upstream and downstream of a single uORF depending on uORF features. Paradoxically, our analysis predicts that reducing ribosome flux upstream of certain uORFs increases initiation downstream. The model supports the derepression of downstream translation as a general mechanism of uORF-mediated stress resistance. It predicts that stress resistance can be achieved with long slowly decoded uORFs that do not favor translation reinitiation and that start with initiators of low leakiness.en
dc.description.sponsorshipNational Science Foundation (DMS-1413223); Russian Science Foundation (RSF16-14-10065)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide32563
dc.identifier.citationAndreev, D. E., Arnold, M., Kiniry, S. J., Loughran, G., Michel, A. M., Rachinskii, D. and Baranov, P. V. (2018) 'TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response', eLife, 7, e32563 (20pp). doi: 10.7554/eLife.32563en
dc.identifier.doi10.7554/eLife.32563
dc.identifier.endpage20
dc.identifier.issn2050-084X
dc.identifier.journaltitleeLifeen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/6829
dc.identifier.volume7
dc.language.isoenen
dc.publisherelifeen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Investigator Programme/12/IA/1335/IE/Development of computational resources for the analysis of Genome Wide Information on Protein Synthesis (GWIPS)./
dc.relation.urihttps://elifesciences.org/articles/32563
dc.rights© 2018, Andreev et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectOpen reading framesen
dc.subjectGene-specific translationen
dc.subjectRibosome profiling revealsen
dc.subjectEukaryotic messenger-RNAsen
dc.subjectIn-vivoen
dc.subjectNucleotide resolutionen
dc.subjectMammalian-cellsen
dc.subjectUpstream orfsen
dc.subjectAug tripletsen
dc.subjectInitiationen
dc.titleTASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress responseen
dc.typeArticle (peer-reviewed)en
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