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

Shimada, Kenji and Filipuzzi, Ireos and Helliwell, Stephen and Studer, Christian and Hoepfner, Dominic and Movva, Rao and Gasser, Susan and Stahl, Michael and Loewith, Robbie (2013) TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks. Molecular Cell, 51 (6). pp. 829-839. ISSN 1097-2765

Abstract

A chemicogenetic screen in budding yeast strains with weakened replication stress response has yielded an inhibitor of TOR Complexes 1 and 2 that selectively enhances the sensitivity of sgs1 cells to hydroxyurea and camptothecin. Surprisingly, the inhibitor was strongly synthetic lethal in combination with low levels of either the break-inducing antibiotic Zeocin, or ionizing irradiation, in both wild-type and mutant backgrounds. Yeast chromosomes break into 0.1-0.5-Mb fragments during a 60-min exposure to Zeocin, when TORC2, but not TORC1, was repressed. Inhibition of the effector kinases downstream of TORC2, Ypk1/Ypk2, conferred similar synergistic effects in the presence of low levels of Zeocin. Given that the actin cytoskeleton is under Ypk1/2 control, we tested the effects of Latrunculin A or jasplakinolide, and found that these phenocopy the effects of TORC2 inhibition on Zeocin, while calcineurin-sensitive transcription pathways do not. This suggests that TORC2-regulated actin filament stabilization promotes survival of low-level DNA damage.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10398

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