TORC2 Signaling Pathway Guarantees Genome Stability in the Face of DNA Strand Breaks
Copyright policy )TORC2 Signaling Pathway Guarantees Genome Stability in the Face of DNA Strand Breaks
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.
- Novartis Institutes for BioMedical Research Switzerland
- University of Geneva Switzerland
- Novartis (Switzerland) Switzerland
- Friedrich Miescher Institute Switzerland
- University of Basel Switzerland
DNA Replication, 570, Ionizing, Saccharomyces cerevisiae Proteins, 590, Actins/antagonists & inhibitors/metabolism, Heterocyclic/pharmacology, Bleomycin/pharmacology, Mechanistic Target of Rapamycin Complex 2, Saccharomyces cerevisiae, Chromosomes, Genomic Instability, Saccharomyces cerevisiae/genetics, Bridged Bicyclo Compounds, Bleomycin, Glycogen Synthase Kinase 3, Radiation, Ionizing, Glycogen Synthase Kinase 3/metabolism, Molecular Biology, Chromosomes/drug effects/genetics/radiation effects, Saccharomyces cerevisiae Proteins/antagonists & inhibitors/genetics/metabolism, Radiation, Signal Transduction/drug effects/radiation effects, TOR Serine-Threonine Kinases, Genomic Instability/drug effects/radiation effects, Cell Biology, Thiazolidines/pharmacology, Bridged Bicyclo Compounds, Heterocyclic, Multiprotein Complexes/antagonists & inhibitors/genetics/metabolism, Actins, Transcription Factors/antagonists & inhibitors/genetics/metabolism, Multiprotein Complexes, DNA Replication/drug effects/radiation effects, Thiazolidines, DNA Damage/genetics, TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism, DNA Damage, Signal Transduction, Transcription Factors, ddc: ddc:590, ddc: ddc:570
DNA Replication, 570, Ionizing, Saccharomyces cerevisiae Proteins, 590, Actins/antagonists & inhibitors/metabolism, Heterocyclic/pharmacology, Bleomycin/pharmacology, Mechanistic Target of Rapamycin Complex 2, Saccharomyces cerevisiae, Chromosomes, Genomic Instability, Saccharomyces cerevisiae/genetics, Bridged Bicyclo Compounds, Bleomycin, Glycogen Synthase Kinase 3, Radiation, Ionizing, Glycogen Synthase Kinase 3/metabolism, Molecular Biology, Chromosomes/drug effects/genetics/radiation effects, Saccharomyces cerevisiae Proteins/antagonists & inhibitors/genetics/metabolism, Radiation, Signal Transduction/drug effects/radiation effects, TOR Serine-Threonine Kinases, Genomic Instability/drug effects/radiation effects, Cell Biology, Thiazolidines/pharmacology, Bridged Bicyclo Compounds, Heterocyclic, Multiprotein Complexes/antagonists & inhibitors/genetics/metabolism, Actins, Transcription Factors/antagonists & inhibitors/genetics/metabolism, Multiprotein Complexes, DNA Replication/drug effects/radiation effects, Thiazolidines, DNA Damage/genetics, TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism, DNA Damage, Signal Transduction, Transcription Factors, ddc: ddc:590, ddc: ddc:570
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