Abstract

Chromatin instability and protein homeostasis (proteostasis) stress are two well-established hallmarks of aging, which have been considered largely independent of each other. Using microfluidics and single-cell imaging approaches, we observed that, during the replicative aging of S. cerevisiae, a challenge to proteostasis occurs specifically in the fraction of cells with decreased stability within the ribosomal DNA (rDNA). A screen of 170 yeast RNA-binding proteins identified ribosomal RNA (rRNA)-binding proteins as the most enriched group that aggregate upon a decrease in rDNA stability induced by inhibition of a conserved lysine deacetylase Sir2. Further, loss of rDNA stability induces age-dependent aggregation of rRNA-binding proteins through aberrant overproduction of rRNAs. These aggregates contribute to age-induced proteostasis decline and limit cellular lifespan. Our findings reveal a mechanism underlying the interconnection between chromatin instability and proteostasis stress and highlight the importance of cell-to-cell variability in aging processes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source data have been provided for Figure 2.

Article and author information

Author details

  1. Julie Paxman

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhen Zhou

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0706-9089
  3. Richard O'Laughlin

    Department of Bioengineering, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuting Liu

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yang Li

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5714-0416
  6. Wanying Tian

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hetian Su

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yanfei Jiang

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Shayna E Holness

    Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6730-0583
  10. Elizabeth Stasiowski

    Department of Bioengineering, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lev S Tsimring

    Synthetic Biology Institute, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0709-3548
  12. Lorraine Pillus

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8818-5227
  13. Jeff Hasty

    Synthetic Biology Institute, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Nan Hao

    Department of Molecular Biology, University of California, San Diego, La Jolla, United States
    For correspondence
    nhao@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2857-4789

Funding

National Institutes of Health (R01AG056440)

  • Lev S Tsimring
  • Lorraine Pillus
  • Jeff Hasty
  • Nan Hao

National Institutes of Health (R01GM111458)

  • Nan Hao

National Institutes of Health (R01AG068112)

  • Nan Hao

National Institutes of Health (T32GM007240)

  • Julie Paxman

National Science Foundation (MCB1716841)

  • Lorraine Pillus

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

Copyright

© 2022, Paxman 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. Julie Paxman
  2. Zhen Zhou
  3. Richard O'Laughlin
  4. Yuting Liu
  5. Yang Li
  6. Wanying Tian
  7. Hetian Su
  8. Yanfei Jiang
  9. Shayna E Holness
  10. Elizabeth Stasiowski
  11. Lev S Tsimring
  12. Lorraine Pillus
  13. Jeff Hasty
  14. Nan Hao
(2022)
Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis
eLife 11:e75978.
https://doi.org/10.7554/eLife.75978

Share this article

https://doi.org/10.7554/eLife.75978

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