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Transcription errors induce proteotoxic stress and shorten cellular lifespan

Author

Listed:
  • Marc Vermulst

    (University of North Carolina
    Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia)

  • Ashley S. Denney

    (School of Medicine, University of Colorado)

  • Michael J. Lang

    (University of Michigan)

  • Chao-Wei Hung

    (University of North Carolina)

  • Stephanie Moore

    (University of North Carolina)

  • M. Arthur Moseley

    (Proteomics Core Facility, Duke University)

  • J. Will Thompson

    (Proteomics Core Facility, Duke University)

  • Victoria Madden

    (Microscopy Services Laboratory, School of Medicine, University of North Carolina)

  • Jacob Gauer

    (University of North Carolina)

  • Katie J. Wolfe

    (University of North Carolina)

  • Daniel W. Summers

    (and Hope Center for Neurological Disorders, Washington University School of Medicine)

  • Jennifer Schleit

    (University of Washington)

  • George L. Sutphin

    (University of Washington)

  • Suraiya Haroon

    (Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia)

  • Agnes Holczbauer

    (Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia)

  • Joanne Caine

    (CSIRO)

  • James Jorgenson

    (University of North Carolina)

  • Douglas Cyr

    (University of North Carolina)

  • Matt Kaeberlein

    (University of Washington)

  • Jeffrey N. Strathern

    (Center for Cancer Research, National Cancer Institute)

  • Mara C. Duncan

    (University of Michigan)

  • Dorothy A. Erie

    (University of North Carolina
    Curriculum in Applied Sciences and Engineering, University of North Carolina)

Abstract

Transcription errors occur in all living cells; however, it is unknown how these errors affect cellular health. To answer this question, we monitor yeast cells that are genetically engineered to display error-prone transcription. We discover that these cells suffer from a profound loss in proteostasis, which sensitizes them to the expression of genes that are associated with protein-folding diseases in humans; thus, transcription errors represent a new molecular mechanism by which cells can acquire disease phenotypes. We further find that the error rate of transcription increases as cells age, suggesting that transcription errors affect proteostasis particularly in aging cells. Accordingly, transcription errors accelerate the aggregation of a peptide that is implicated in Alzheimer's disease, and shorten the lifespan of cells. These experiments reveal a previously unappreciated role for transcriptional fidelity in cellular health and aging.

Suggested Citation

  • Marc Vermulst & Ashley S. Denney & Michael J. Lang & Chao-Wei Hung & Stephanie Moore & M. Arthur Moseley & J. Will Thompson & Victoria Madden & Jacob Gauer & Katie J. Wolfe & Daniel W. Summers & Jenni, 2015. "Transcription errors induce proteotoxic stress and shorten cellular lifespan," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9065
    DOI: 10.1038/ncomms9065
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    Cited by:

    1. Claire S. Chung & Yi Kou & Sarah J. Shemtov & Bert M. Verheijen & Ilse Flores & Kayla Love & Ashley Dosso & Max A. Thorwald & Yuchen Liu & Daniel Hicks & Yingwo Sun & Renaldo G. Toney & Lucy Carrillo , 2024. "Transcript errors generate amyloid-like proteins in human cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Claire Chung & Bert M. Verheijen & Zoe Navapanich & Eric G. McGann & Sarah Shemtov & Guan-Ju Lai & Payal Arora & Atif Towheed & Suraiya Haroon & Agnes Holczbauer & Sharon Chang & Zarko Manojlovic & St, 2023. "Evolutionary conservation of the fidelity of transcription," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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