1. Biochemistry and Chemical Biology

Translation of 5' leaders is pervasive in genes resistant to eIF2 repression

  1. Dmitry E Andreev
  2. Patrick BF O'Connor
  3. Ciara Fahey
  4. Elaine M Kenny
  5. Ilya M Terenin
  6. Sergey E Dmitriev
  7. Paul Cormican
  8. Derek W Morris
  9. Ivan N Shatsky
  10. Pavel V Baranov  Is a corresponding author
  1. Lomonosov Moscow State University, Russia
  2. University College Cork, Ireland
  3. Trinity College Dublin, Ireland
https://doi.org/10.7554/eLife.03971
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  1. Dmitry E Andreev
  2. Patrick BF O'Connor
  3. Ciara Fahey
  4. Elaine M Kenny
  5. Ilya M Terenin
  6. Sergey E Dmitriev
  7. Paul Cormican
  8. Derek W Morris
  9. Ivan N Shatsky
  10. Pavel V Baranov
(2015)
Translation of 5' leaders is pervasive in genes resistant to eIF2 repression
eLife 4:e03971.
https://doi.org/10.7554/eLife.03971
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Abstract

Eukaryotic cells rapidly reduce protein synthesis in response to various stress conditions. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eIF2. However, the persistent translation of certain mRNAs is required for deployment of an adequate stress response. We carried out ribosome profiling of cultured human cells under conditions of severe stress induced with sodium arsenite. Although this led to a ~4.5-fold general translational repression, the protein coding ORFs of certain individual mRNAs exhibited resistance to the inhibition. Nearly all resistant transcripts possess at least one efficiently translated uORF that repress translation of the main coding ORF under normal conditions. Site specific mutagenesis of two identified stress resistant mRNAs (PPP1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control in both cases. Phylogenetic analysis suggests that at least two regulatory uORFs (namely in SLC35A4 and MIEF1) encode functional protein products.

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  1. Dmitry E Andreev

    Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
    Competing interests
    The authors declare that no competing interests exist.

  2. Patrick BF O'Connor

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

  3. Ciara Fahey

    Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.

  4. Elaine M Kenny

    Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.

  5. Ilya M Terenin

    Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
    Competing interests
    The authors declare that no competing interests exist.

  6. Sergey E Dmitriev

    Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
    Competing interests
    The authors declare that no competing interests exist.

  7. Paul Cormican

    Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.

  8. Derek W Morris

    Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.

  9. Ivan N Shatsky

    Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
    Competing interests
    The authors declare that no competing interests exist.

  10. Pavel V Baranov

    School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
    For correspondence
    brave.oval.pan@gmail.com
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, 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. Patrick BF O'Connor
  3. Ciara Fahey
  4. Elaine M Kenny
  5. Ilya M Terenin
  6. Sergey E Dmitriev
  7. Paul Cormican
  8. Derek W Morris
  9. Ivan N Shatsky
  10. Pavel V Baranov
(2015)
Translation of 5' leaders is pervasive in genes resistant to eIF2 repression
eLife 4:e03971.
https://doi.org/10.7554/eLife.03971

Share this article

https://doi.org/10.7554/eLife.03971

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Further reading

    1. Chromosomes and Gene Expression
    2. Computational and Systems Biology

    TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response

    Dmitry E Andreev, Maxim Arnold ... Pavel V Baranov
    Research Advance Updated

    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.