en
Scientific article
English

TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks

Published inMolecular Cell, vol. 51, no. 6, p. 829-839
Publication date2013
Abstract

A chemicogenetic screen was performed in budding yeast mutants that have a weakened replication stress response. This identified an inhibitor of target of rapamycin (TOR) complexes 1 and 2 that selectively enhances the sensitivity of sgs1Δ cells to hydroxyurea and camptothecin. More importantly, the inhibitor has strong synthetic lethality in combination with either the break-inducing antibiotic Zeocin or ionizing radiation, independent of the strain background. Lethality correlates with a rapid fragmentation of chromosomes that occurs only when TORC2, but not TORC1, is repressed. Genetic inhibition of Tor2 kinase, or its downstream effector kinases Ypk1/Ypk2, conferred similar synergistic effects in the presence of Zeocin. Given that Ypk1/Ypk2 controls the actin cytoskeleton, we tested the effects of actin modulators latrunculin A and jasplakinolide. These phenocopy TORC2 inhibition on Zeocin, although modulation of calcineurin-sensitive transcription does not. These results implicate TORC2-mediated actin filament regulation in the survival of low levels of DNA damage.

Keywords
  • Actins/antagonists & inhibitors/metabolism
  • Bleomycin/pharmacology
  • Bridged Bicyclo Compounds
  • Heterocyclic/pharmacology
  • Chromosomes/drug effects/genetics/radiation effects
  • DNA Damage/genetics
  • DNA Replication/drug effects/radiation effects
  • Genomic Instability/drug effects/radiation effects
  • Glycogen Synthase Kinase 3/metabolism
  • Mechanistic Target of Rapamycin Complex 2
  • Multiprotein Complexes/antagonists & inhibitors/genetics/metabolism
  • Radiation
  • Ionizing
  • Saccharomyces cerevisiae/genetics
  • Saccharomyces cerevisiae Proteins/antagonists & inhibitors/genetics/metabolism
  • Signal Transduction/drug effects/radiation effects
  • TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
  • Thiazolidines/pharmacology
  • Transcription Factors/antagonists & inhibitors/genetics/metabolism
Research group
Citation (ISO format)
SHIMADA, Kenji et al. TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks. In: Molecular Cell, 2013, vol. 51, n° 6, p. 829–839. doi: 10.1016/j.molcel.2013.08.019
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal1097-2765
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