TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the Integrated Stress Response
- University College Cork, Ireland
- University of Texas at Dallas, United States
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 resistant to this inhibition possess translated uORFs, and that in some cases a single uORF is sufficient for the resistance (Andreev et al., 2015). 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 start with initiators of low leakiness.
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All data generated during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2 to 7.
Article and author information
Author details
Funding
Science Foundation Ireland (12/IA/1335))
- Pavel V Baranov
National Science Foundation (DMS-1413223)
- Dmitry Rachinskiy
Russian Science Foundation (RSF16-14-10065)
- Dmitry E Andreev
Irish Research Council
- Stephen J Kiniry
- Audrey M Michel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Andreev et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the Integrated Stress Response
eLife 7:e32563.
https://doi.org/10.7554/eLife.32563
