title: TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks.
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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimada
authors.forename: Ireos
authors.initials: I
authors.lastname: Filipuzzi
authors.forename: Michael
authors.initials: M
authors.lastname: Stahl
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Helliwell
authors.forename: Christian
authors.initials: C
authors.lastname: Studer
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.forename: Andrew
authors.initials: A
authors.lastname: Seeber
authors.forename: Robbie
authors.initials: R
authors.lastname: Loewith
authors.forename: N Rao
authors.initials: NR
authors.lastname: Movva
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gasser
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001761:Bleomycin / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002875:Chromosomes / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011839:Radiation, Ionizing; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; C561842:TORC1 protein complex, S cerevisiae; D053778:Thiazolidines; D014157:Transcription Factors; D001761:Bleomycin; C105427:Zeocin; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C068124:MCK1 protein, S cerevisiae; C037067:latrunculin A