TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response
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.contributor.funder | Irish Research Council | |
dc.contributor.funder | Russian Science Foundation | |
dc.contributor.funder | National Science Foundation | |
dc.contributor.funder | Science Foundation Ireland | |
dc.date.accessioned | 2018-09-20T15:53:39Z | |
dc.date.available | 2018-09-20T15:53:39Z | |
dc.date.issued | 2018 | |
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.description.status | Peer reviewed | en |
dc.description.version | Published Version | en |
dc.format.mimetype | application/pdf | en |
dc.identifier.articleid | e32563 | |
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.doi | 10.7554/eLife.32563 | |
dc.identifier.endpage | 20 | |
dc.identifier.issn | 2050-084X | |
dc.identifier.journaltitle | eLife | en |
dc.identifier.startpage | 1 | |
dc.identifier.uri | https://hdl.handle.net/10468/6829 | |
dc.identifier.volume | 7 | |
dc.language.iso | en | en |
dc.publisher | elife | en |
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)./ | |
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 |
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