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.
Mesh Terms:
Actins, Bicyclo Compounds, Heterocyclic, Bleomycin, Chromosomes, DNA Damage, DNA Replication, Genomic Instability, Glycogen Synthase Kinase 3, Multiprotein Complexes, Radiation, Ionizing, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, TOR Serine-Threonine Kinases, Thiazolidines, Transcription Factors
Mol. Cell
Date: Sep. 26, 2013
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