TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response
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 c...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/32563 |
| _version_ | 1818019816796061696 |
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| author | Dmitry E Andreev Maxim Arnold Stephen J Kiniry Gary Loughran Audrey M Michel Dmitrii Rachinskii Pavel V Baranov |
| author_facet | Dmitry E Andreev Maxim Arnold Stephen J Kiniry Gary Loughran Audrey M Michel Dmitrii Rachinskii Pavel V Baranov |
| author_sort | Dmitry E Andreev |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:56:32Z |
| format | Article |
| id | doaj.art-37d6e8bce4cc4482ab33c3de14246b98 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:56:32Z |
| publishDate | 2018-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-37d6e8bce4cc4482ab33c3de14246b982022-12-22T02:05:01ZengeLife Sciences Publications LtdeLife2050-084X2018-06-01710.7554/eLife.32563TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress responseDmitry E Andreev0Maxim Arnold1Stephen J Kiniry2Gary Loughran3https://orcid.org/0000-0002-2683-5597Audrey M Michel4Dmitrii Rachinskii5Pavel V Baranov6https://orcid.org/0000-0001-9017-0270School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, RussiaDepartment of Mathematical Sciences, The University of Texas at Dallas, Richardson, United StatesSchool of Biochemistry and Cell Biology, University College Cork, Cork, IrelandSchool of Biochemistry and Cell Biology, University College Cork, Cork, IrelandSchool of Biochemistry and Cell Biology, University College Cork, Cork, IrelandDepartment of Mathematical Sciences, The University of Texas at Dallas, Richardson, United StatesSchool of Biochemistry and Cell Biology, University College Cork, Cork, IrelandTranslation 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.https://elifesciences.org/articles/32563uORFTASEPmRNAintegrated stress responsetranslationeIF2 |
| spellingShingle | Dmitry E Andreev Maxim Arnold Stephen J Kiniry Gary Loughran Audrey M Michel Dmitrii Rachinskii Pavel V Baranov TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response eLife uORF TASEP mRNA integrated stress response translation eIF2 |
| title | TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response |
| title_full | TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response |
| title_fullStr | TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response |
| title_full_unstemmed | TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response |
| title_short | TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response |
| title_sort | tasep modelling provides a parsimonious explanation for the ability of a single uorf to derepress translation during the integrated stress response |
| topic | uORF TASEP mRNA integrated stress response translation eIF2 |
| url | https://elifesciences.org/articles/32563 |
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