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.
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Article Synopsis
- TOR kinases are crucial for nutrient signaling and cell growth, organized into TORC1 and TORC2 complexes.
- In budding yeast, TORC2 is particularly important for regulating growth rate and cell size, but how it functions is not fully understood.
- Researchers discovered that the kinases Yck1 and Yck2 significantly impact the phosphorylation and localization of Mss4, a key player in TORC2 signaling, but their inhibition has minor effects on well-characterized pathways, indicating a potential role in less defined TORC2 functions.
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