TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the Integrated Stress Response

  1. Dmitry E Andreev
  2. Maxim Arnold
  3. Stephen J Kiniry
  4. Gary Loughran
  5. Audrey M Michel
  6. Dmitry Rachinskiy  Is a corresponding author
  7. Pavel V Baranov  Is a corresponding author
  1. University College Cork, Ireland
  2. 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.

Data availability

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

  1. Dmitry E Andreev

    School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  2. Maxim Arnold

    Department of Mathematical Sciences, University of Texas at Dallas, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Stephen J Kiniry

    School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  4. Gary Loughran

    School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2683-5597
  5. Audrey M Michel

    School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  6. Dmitry Rachinskiy

    Department of Mathematical Sciences, University of Texas at Dallas, Dallas, United States
    For correspondence
    Dmitry.Rachinskiy@utdallas.edu
    Competing interests
    The authors declare that no competing interests exist.
  7. Pavel V Baranov

    School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
    For correspondence
    p.baranov@ucc.ie
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9017-0270

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.

Reviewing Editor

  1. Nahum Sonenberg, McGill University, Canada

Publication history

  1. Received: October 17, 2017
  2. Accepted: June 21, 2018
  3. Accepted Manuscript published: June 22, 2018 (version 1)
  4. Version of Record published: July 5, 2018 (version 2)

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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  1. Dmitry E Andreev
  2. Maxim Arnold
  3. Stephen J Kiniry
  4. Gary Loughran
  5. Audrey M Michel
  6. Dmitry Rachinskiy
  7. Pavel V Baranov
(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.
https://doi.org/10.7554/eLife.32563
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