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Nat Commun. 2015 Aug 25;6:8065. doi: 10.1038/ncomms9065.

Transcription errors induce proteotoxic stress and shorten cellular lifespan.

Author information

1
Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
2
Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
3
School of Medicine, University of Colorado, Denver, Colorado 80217, USA.
4
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
5
Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
6
Proteomics Core Facility, Duke University, Durham, North Carolina 27710, USA.
7
Microscopy Services Laboratory, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
8
Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
9
Department of Developmental Biology, and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
10
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
11
CSIRO, Department of Materials Science and Engineering, Parkville 3052, Australia.
12
Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA.
13
Department of Chemistry, Curriculum in Applied Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

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.

PMID:
26304740
PMCID:
PMC4684168
DOI:
10.1038/ncomms9065
[Indexed for MEDLINE]
Free PMC Article

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