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Chemical-Genetic Characterization of TORC2 in Yeast


As the clinical focus of cancer therapeutics shift from systemic toxins to targeted therapy, the ability to systematically identify promising candidates for multi-targeted cancer therapy is an increasing concern. Since screening for epistatic phenotypes offers a direct analog to the theoretical regimes used to evaluate synergistic activity of multi-targeted chemotherapy, high-throughput yeast genetics of the nutrient signaling pathway was explored in order to better characterize the signaling network, and discover candidates that synergize with the TOR kinase. Epistatic profiling of S. pombe and S. cerevisiae showed a high degree of network and functional conservation between the two species of yeast and to metazoans which was used to identify members of the TOR signaling network in yeast. Further, we developed the first method to selectively inhibit TOR complex 2 using pharmacology. We use this tool to profile the signaling network of TORC2 and show that this complex plays a regulatory role in the pentose phosphate pathway (PPP) that furnishes nucleotides and amino acids that are required for ribosome biogenesis.

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