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.
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.
- Pavel V Baranov
- Dmitry Rachinskiy
- Dmitry E Andreev
- 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.
- Nahum Sonenberg, McGill University, Canada
© 2018, Andreev et al.
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