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.author Andreev, Dmitry E.
dc.contributor.author Arnold, Maxim
dc.contributor.author Kiniry, Stephen J.
dc.contributor.author Loughran, Gary
dc.contributor.author Michel, Audrey M.
dc.contributor.author Rachinskii, Dmitrii
dc.contributor.author Baranov, Pavel V.
dc.date.accessioned 2018-09-20T15:53:39Z
dc.date.available 2018-09-20T15:53:39Z
dc.date.issued 2018
dc.identifier.citation Andreev, 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.32563 en
dc.identifier.volume 7
dc.identifier.startpage 1
dc.identifier.endpage 20
dc.identifier.issn 2050-084X
dc.identifier.uri http://hdl.handle.net/10468/6829
dc.identifier.doi 10.7554/eLife.32563
dc.description.abstract Translation 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.sponsorship National Science Foundation (DMS-1413223); Russian Science Foundation (RSF16-14-10065) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher elife en
dc.relation.uri https://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.uri https://creativecommons.org/licenses/by/4.0/
dc.subject Open reading frames en
dc.subject Gene-specific translation en
dc.subject Ribosome profiling reveals en
dc.subject Eukaryotic messenger-RNAs en
dc.subject In-vivo en
dc.subject Nucleotide resolution en
dc.subject Mammalian-cells en
dc.subject Upstream orfs en
dc.subject Aug triplets en
dc.subject Initiation en
dc.title TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Pavel V. Baranov, Biochemistry & Cell Biology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: P.Baranov@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Irish Research Council
dc.contributor.funder Russian Science Foundation
dc.contributor.funder National Science Foundation
dc.contributor.funder Science Foundation Ireland
dc.description.status Peer reviewed en
dc.identifier.journaltitle eLife en
dc.internal.IRISemailaddress p.baranov@ucc.ie en
dc.identifier.articleid e32563
dc.relation.project info: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)./


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© 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. Except where otherwise noted, this item's license is described as © 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.
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