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

Kenji Shimada; Ireos Filipuzzi; Michael Stahl; Stephen B Helliwell; Christian Studer; Dominic Hoepfner; Andrew Seeber; Robbie Loewith; N Rao Movva; Susan M Gasser

doi:10.1016/j.molcel.2013.08.019

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

Mol Cell. 2013 Sep 26;51(6):829-39. doi: 10.1016/j.molcel.2013.08.019. Epub 2013 Sep 12.

Authors

Kenji Shimada¹, Ireos Filipuzzi, Michael Stahl, Stephen B Helliwell, Christian Studer, Dominic Hoepfner, Andrew Seeber, Robbie Loewith, N Rao Movva, Susan M Gasser

Affiliation

¹ Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.

PMID: 24035500
DOI: 10.1016/j.molcel.2013.08.019

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / antagonists & inhibitors
Actins / metabolism
Bleomycin / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Chromosomes / drug effects
Chromosomes / genetics
Chromosomes / radiation effects
DNA Damage / genetics
DNA Replication / drug effects
DNA Replication / radiation effects
Genomic Instability* / drug effects
Genomic Instability* / radiation effects
Glycogen Synthase Kinase 3 / metabolism
Mechanistic Target of Rapamycin Complex 2
Multiprotein Complexes / antagonists & inhibitors
Multiprotein Complexes / genetics*
Multiprotein Complexes / metabolism
Radiation, Ionizing
Saccharomyces cerevisiae / genetics*
Saccharomyces cerevisiae Proteins / antagonists & inhibitors
Saccharomyces cerevisiae Proteins / genetics*
Saccharomyces cerevisiae Proteins / metabolism
Signal Transduction / drug effects
Signal Transduction / radiation effects
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism
Thiazolidines / pharmacology
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

Actins
Bridged Bicyclo Compounds, Heterocyclic
Multiprotein Complexes
Saccharomyces cerevisiae Proteins
TORC1 protein complex, S cerevisiae
Thiazolidines
Transcription Factors
Bleomycin
Zeocin
Mechanistic Target of Rapamycin Complex 2
TOR Serine-Threonine Kinases
Glycogen Synthase Kinase 3
MCK1 protein, S cerevisiae
latrunculin A