Nature Biotechnology
22, 62 - 69 (2003)
Published online: 7 December 2003; | doi:10.1038/nbt919
Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathwaysAinslie B Parsons1, 2, Renée L Brost2, Huiming Ding2, Zhijian Li1, 2, Chaoying Zhang3, Bilal Sheikh2, Grant W Brown3, Patricia M Kane4, Timothy R Hughes1, 2
& Charles Boone1, 21
Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1L6, Canada. 2
Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada. 3
Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1L6, Canada. 4
Department of Biochemistry, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
Correspondence should be addressed to Charles Boone charlie.boone@utoronto.caBioactive compounds can be valuable research tools and drug leads, but it is often difficult to identify their mechanism of action or cellular target. Here we investigate the potential for integration of chemical-genetic and genetic interaction data to reveal information about the pathways and targets of inhibitory compounds. Taking advantage of the existing complete set of yeast haploid deletion mutants, we generated drug-hypersensitivity (chemical-genetic) profiles for 12 compounds. In addition to a set of compound-specific interactions, the chemical-genetic profiles identified a large group of genes required for multidrug resistance. In particular, yeast mutants lacking a functional vacuolar H+-ATPase show multidrug sensitivity, a phenomenon that may be conserved in mammalian cells. By filtering chemical-genetic profiles for the multidrug-resistant genes and then clustering the compound-specific profiles with a compendium of large-scale genetic interaction profiles, we were able to identify target pathways or proteins. This method thus provides a powerful means for inferring mechanism of action.
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