Shimada, Kenji, Filipuzzi, Ireos, Helliwell, Stephen, Studer, Christian, Hoepfner, Dominic, Movva, Rao, Gasser, Susan, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed/?term...
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed/?term...
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/10398