Transcription errors induce proteotoxic stress and shorten cellular lifespan

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, Jennifer Schleit, George L. Sutphin, Suraiya Haroon, Agnes Holczbauer, Joanne Caine, James Jorgenson, Douglas Cyr, Matt Kaeberlein, Jeffrey N. Strathern, Mara C. Duncan and Dorothy A. Erie ()
Additional contact information
Marc Vermulst: University of North Carolina
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

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9065

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