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

Shimada, Kenji
Filipuzzi, Ireos
Helliwell, Stephen B
Studer, Christian
Hoepfner, Dominic
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Published in Molecular Cell. 2013, vol. 51, no. 6, p. 829-839
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/metabolismBleomycin/pharmacologyBridged Bicyclo CompoundsHeterocyclic/pharmacologyChromosomes/drug effects/genetics/radiation effectsDNA Damage/geneticsDNA Replication/drug effects/radiation effectsGenomic Instability/drug effects/radiation effectsGlycogen Synthase Kinase 3/metabolismMechanistic Target of Rapamycin Complex 2Multiprotein Complexes/antagonists & inhibitors/genetics/metabolismRadiationIonizingSaccharomyces cerevisiae/geneticsSaccharomyces cerevisiae Proteins/antagonists & inhibitors/genetics/metabolismSignal Transduction/drug effects/radiation effectsTOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolismThiazolidines/pharmacologyTranscription Factors/antagonists & inhibitors/genetics/metabolism
PMID: 24035500
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Research group Groupe Loewith
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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 https://archive-ouverte.unige.ch/unige:103232

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Deposited on : 2018-03-27

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