N6-methyladenosine (m6A) reader Pho92 is recruited co-transcriptionally and couples translation to mRNA decay to promote meiotic fitness in yeast

Abstract

N6-methyladenosine (m6A) RNA modification impacts mRNA fate primarily via reader proteins, which dictate processes in development, stress, and disease. Yet little is known about m6A function in Saccharomyces cerevisiae, which occurs solely during early meiosis. Here we perform a multifaceted analysis of the m6A reader protein Pho92/Mrb1. Cross-linking immunoprecipitation analysis reveals that Pho92 associates with the 3’end of meiotic mRNAs in both an m6A-dependent and independent manner. Within cells, Pho92 transitions from the nucleus to the cytoplasm, and associates with translating ribosomes. In the nucleus Pho92 associates with target loci through its interaction with transcriptional elongator Paf1C. Functionally, we show that Pho92 promotes and links protein synthesis to mRNA decay. As such, the Pho92-mediated m6A-mRNA decay is contingent on active translation and the CCR4-NOT complex. We propose that the m6A reader Pho92 is loaded co-transcriptionally to facilitate protein synthesis and subsequent decay of m6A modified transcripts, and thereby promotes meiosis.

Data availability

The miCLIP, iCLIP and RNA-seq RAW and processed data are available to review GEO accession GSE193561:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE193561

The following data sets were generated

Article and author information

Author details

  1. Radhika A Varier

    The Francis Crick Institute, London, United Kingdom
    For correspondence
    radhikaav@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1302-3159
  2. Theodora Sideri

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5674-0804
  3. Charlotte Capitanchik

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Zornitsa Manova

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Enrica Calvani

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Alice Rossi

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Raghu R Edupuganti

    Department of Molecular Biology, Radboud University Nijmegen, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Imke Ensinck

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Vincent WC Chan

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6638-5498
  10. Harshil Patel

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Joanna Kirkpatrick

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Peter Faull

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Ambrosius P Snijders

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Michiel Vermeulen

    Department of Molecular Biology, Radboud University Nijmegen, Nijmegen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  15. Markus Ralser

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Jernej Ule

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2452-4277
  17. Nicholas M Luscombe

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. Folkert Jacobus van Werven

    The Francis Crick Institute, London, United Kingdom
    For correspondence
    folkert.vanwerven@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6685-2084

Funding

Wellcome Trust (FC001203)

  • Radhika A Varier
  • Theodora Sideri
  • Zornitsa Manova
  • Alice Rossi
  • Imke Ensinck
  • Folkert Jacobus van Werven

Cancer Research UK (FC001203)

  • Radhika A Varier
  • Theodora Sideri
  • Zornitsa Manova
  • Alice Rossi
  • Imke Ensinck
  • Folkert Jacobus van Werven

Medical Research Council (FC001203)

  • Radhika A Varier
  • Theodora Sideri
  • Zornitsa Manova
  • Alice Rossi
  • Imke Ensinck
  • Folkert Jacobus van Werven

Wellcome Trust (FC010110)

  • Charlotte Capitanchik
  • Nicholas M Luscombe

Cancer Research UK (FC010110)

  • Charlotte Capitanchik
  • Nicholas M Luscombe

Medical Research Council (FC010110)

  • Charlotte Capitanchik
  • Nicholas M Luscombe

Medical Research Council (FC001134)

  • Enrica Calvani
  • Markus Ralser

Cancer Research UK (FC001134)

  • Enrica Calvani
  • Markus Ralser

Dutch Cancer Society

  • Raghu R Edupuganti
  • Michiel Vermeulen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Timothy W Nilsen, Case Western Reserve University, United States

Publication history

  1. Received: October 7, 2022
  2. Accepted: November 13, 2022
  3. Accepted Manuscript published: November 24, 2022 (version 1)
  4. Accepted Manuscript updated: November 28, 2022 (version 2)

Copyright

© 2022, Varier 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. Radhika A Varier
  2. Theodora Sideri
  3. Charlotte Capitanchik
  4. Zornitsa Manova
  5. Enrica Calvani
  6. Alice Rossi
  7. Raghu R Edupuganti
  8. Imke Ensinck
  9. Vincent WC Chan
  10. Harshil Patel
  11. Joanna Kirkpatrick
  12. Peter Faull
  13. Ambrosius P Snijders
  14. Michiel Vermeulen
  15. Markus Ralser
  16. Jernej Ule
  17. Nicholas M Luscombe
  18. Folkert Jacobus van Werven
(2022)
N6-methyladenosine (m6A) reader Pho92 is recruited co-transcriptionally and couples translation to mRNA decay to promote meiotic fitness in yeast
eLife 11:e84034.
https://doi.org/10.7554/eLife.84034

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