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dc.contributor.authorAndreev, D. E.
dc.contributor.authorArnold, Maxim
dc.contributor.authorKiniry, S. J.
dc.contributor.authorLoughran, G.
dc.contributor.authorMichel, A. M.
dc.contributor.authorRachinskii, Dmitry I.
dc.contributor.authorBaranov, P. V.
dc.date.accessioned2019-10-07T22:43:01Z
dc.date.available2019-10-07T22:43:01Z
dc.date.created2018-07-05
dc.identifier.issn2050-084X
dc.identifier.urihttps://hdl.handle.net/10735.1/6970
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. © Andreev et al.
dc.description.sponsorshipScience Foundation Ireland (12/IA/1335); National Science Foundation (DMS-1413223); Russian Science Foundation (RSF16-14-10065).
dc.language.isoen
dc.publishereLIFE Sciences Publications Ltd
dc.relation.urihttp://dx.doi.org/10.7554/eLife.32563
dc.rightsCC BY 4.0 (Attribution)
dc.rights©2018 The Authors
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectOpen Reading Frames
dc.subjectMessenger RNA
dc.subjectProteins—Synthesis
dc.subjectHuman beings
dc.titleTASEP Modelling Provides a Parsimonious Explanation for the Ability of a Single uORF to Derepress Translation during the Integrated Stress Response
dc.type.genrearticle
dc.description.departmentSchool of Natural Sciences and Mathematics
dc.identifier.bibliographicCitationAndreev, D. E., M. Arnold, S. J. Kiniry, G. Loughran, et al. 2018. "TASEP modelling provides a parsimonious explanation for the ability of a single uorf to derepress translation during the integrated stress response." eLIFE 7: art. e32563, doi: 10.7554/eLife.32563
dc.source.journaleLIFE
dc.identifier.volume7
dc.contributor.utdAuthorArnold, Maxim
dc.contributor.utdAuthorRachinskii, Dmitry I.
dc.contributor.ISNI0000 0003 5341 0057 (Rachinskii, DI)
dc.contributor.ORCID0000-0002-4500-8394 (Arnold, M)


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