title: Transcription errors induce proteotoxic stress and shorten cellular lifespan.
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.
authors: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.|Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors: Marc
authors: M
authors: Vermulst
authors: School of Medicine, University of Colorado, Denver, Colorado 80217, USA.
authors: Ashley S
authors: AS
authors: Denney
authors: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Michael J
authors: MJ
authors: Lang
authors: Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Chao-Wei
authors: CW
authors: Hung
authors: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Stephanie
authors: S
authors: Moore
authors: Proteomics Core Facility, Duke University, Durham, North Carolina 27710, USA.
authors: M Arthur
authors: MA
authors: Moseley
authors: Proteomics Core Facility, Duke University, Durham, North Carolina 27710, USA.
authors: Arthur M
authors: AM
authors: Mosely
authors: Proteomics Core Facility, Duke University, Durham, North Carolina 27710, USA.
authors: J Will
authors: JW
authors: Thompson
authors: Proteomics Core Facility, Duke University, Durham, North Carolina 27710, USA.
authors: William J
authors: WJ
authors: Thompson
authors: Microscopy Services Laboratory, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Victoria
authors: V
authors: Madden
authors: Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Jacob
authors: J
authors: Gauer
authors: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Katie J
authors: KJ
authors: Wolfe
authors: Department of Developmental Biology, and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors: Daniel W
authors: DW
authors: Summers
authors: Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
authors: Jennifer
authors: J
authors: Schleit
authors: Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
authors: George L
authors: GL
authors: Sutphin
authors: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors: Suraiya
authors: S
authors: Haroon
authors: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors: Agnes
authors: A
authors: Holczbauer
authors: CSIRO, Department of Materials Science and Engineering, Parkville 3052, Australia.
authors: Joanne
authors: J
authors: Caine
authors: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: James
authors: J
authors: Jorgenson
authors: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Douglas
authors: D
authors: Cyr
authors: Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
authors: Matt
authors: M
authors: Kaeberlein
authors: Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA.
authors: Jeffrey N
authors: JN
authors: Strathern
authors: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Mara C
authors: MC
authors: Duncan
authors: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.|Department of Chemistry, Curriculum in Applied Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Dorothy A
authors: DA
authors: Erie
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D012319:RNA Polymerase II / Q000235:genetics; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D014158:Transcription, Genetic
chemical_list: D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D012319:RNA Polymerase II; C511736:RPB1 protein, S cerevisiae; C509257:Rpb9 protein, S cerevisiae