Transcription errors induce proteotoxic stress and shorten cellular lifespan

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Cell Line
  • Cell Survival / genetics
  • Cellular Senescence / genetics*
  • Heat-Shock Proteins / metabolism
  • Molecular Chaperones / metabolism*
  • Mutation
  • Protein Aggregation, Pathological / metabolism*
  • RNA Polymerase II / genetics
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Stress, Physiological*
  • Transcription, Genetic*

Substances

  • Heat-Shock Proteins
  • Molecular Chaperones
  • Saccharomyces cerevisiae Proteins
  • HsP104 protein, S cerevisiae
  • RNA Polymerase II
  • RPB1 protein, S cerevisiae
  • Rpb9 protein, S cerevisiae