TOR regulates cell death induced by telomere dysfunction in budding yeast

PLoS One. 2008;3(10):e3520. doi: 10.1371/journal.pone.0003520. Epub 2008 Oct 24.

Abstract

Telomere dysfunction is known to induce growth arrest (senescence) and cell death. However, the regulation of the senescence-death process is poorly understood. Here using a yeast dysfunctional telomere model cdc13-1, which carries a temperature sensitive-mutant telomere binding protein Cdc13p, we demonstrate that inhibition of TOR (Target of Rapamycin), a central regulator of nutrient pathways for cell growth, prevents cell death, but not growth arrest, induced by inactivation of Cdc13-1p. This function of TOR is novel and separable from its G1 inhibition function, and not associated with alterations in the telomere length, the amount of G-tails, and the telomere position effect (TPE) in cdc13-1 cells. Furthermore, antioxidants were also shown to prevent cell death initiated by inactivation of cdc13-1. Moreover, inhibition of TOR was also shown to prevent cell death induced by inactivation of telomerase in an est1 mutant. Interestingly, rapamycin did not prevent cell death induced by DNA damaging agents such as etoposide and UV. In the aggregate, our results suggest that the TOR signaling pathway is specifically involved in the regulation of cell death initiated by telomere dysfunction.

Publication types

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

MeSH terms

  • Antioxidants / pharmacology
  • Cell Death / drug effects
  • Cell Death / genetics
  • DNA Damage / genetics*
  • DNA Damage / physiology
  • G1 Phase / drug effects
  • G1 Phase / genetics
  • Membrane Potential, Mitochondrial / drug effects
  • Organisms, Genetically Modified
  • Protein Binding / drug effects
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Reactive Oxygen Species / metabolism
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / physiology*
  • Saccharomycetales / genetics
  • Saccharomycetales / metabolism
  • Saccharomycetales / physiology*
  • Signal Transduction / genetics
  • Sirolimus / pharmacology
  • Telomerase / genetics
  • Telomerase / physiology
  • Telomere / drug effects
  • Telomere / genetics
  • Telomere / metabolism
  • Telomere / physiology*
  • Telomere-Binding Proteins / metabolism

Substances

  • Antioxidants
  • Cdc13 protein, S cerevisiae
  • Reactive Oxygen Species
  • Saccharomyces cerevisiae Proteins
  • Telomere-Binding Proteins
  • Protein Serine-Threonine Kinases
  • target of rapamycin protein, S cerevisiae
  • EST1 protein, S cerevisiae
  • Telomerase
  • Sirolimus