Combining chemical genomics screens in yeast to reveal spectrum of effects of chemical inhibition of sphingolipid biosynthesis
department or school: Biochemistry and Molecular Biology, Department of
department or school: Cellular and Physiological Sciences, Department of
department or school: Medicine, Faculty of
department or school: Non UBC
data provider: DSpace
identifier citation: BMC Microbiology. 2009 Jan 14;9(1):9
rights copyright: Kemmer et al.
creator: Kemmer, Danielle
creator: McHardy, Lianne M.
creator: Hoon, Shawn
creator: Rebérioux, Delphine
creator: Giaever, Guri
creator: Nislow, Corey
creator: Roskelley, Cal
creator: Roberge, Michel
issued: 2015-11-05T03:22:39
issued: 2009-01-14
description: Background: Single genome-wide screens for the effect of altered gene dosage on drug sensitivity in the model organism Saccharomyces cerevisiae provide only a partial picture of the mechanism of action of a drug. Results Using the example of the tumor cell invasion inhibitor dihydromotuporamine C, we show that a more complete picture of drug action can be obtained by combining different chemical genomics approaches - analysis of the sensitivity of ρ 0 cells lacking mitochondrial DNA, drug-induced haploinsufficiency, suppression of drug sensitivity by gene overexpression and chemical-genetic synthetic lethality screening using strains deleted of nonessential genes. Killing of yeast by this chemical requires a functional mitochondrial electron-transport chain and cytochrome c heme lyase function. However, we find that it does not require genes associated with programmed cell death in yeast. The chemical also inhibits endocytosis and intracellular vesicle trafficking and interferes with vacuolar acidification in yeast and in human cancer cells. These effects can all be ascribed to inhibition of sphingolipid biosynthesis by dihydromotuporamine C. Conclusion Despite their similar conceptual basis, namely altering drug sensitivity by modifying gene dosage, each of the screening approaches provided a distinct set of information that, when integrated, revealed a more complete picture of the mechanism of action of a drug on cells.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/55185
note: ralssBioMed CentBMC MicrobiologyOpen AcceResearch articleCombining chemical genomics screens in yeast to reveal spectrum of effects of chemical inhibition of sphingolipid biosynthesisDanielle Kemmer1, Lianne M McHardy1, Shawn Hoon2, Delphine Rebérioux1, Guri Giaever3,4,5, Corey Nislow4,5,6, Calvin D Roskelley7 and Michel Roberge*1Address: 1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada, 2Stanford Genome Technology Center, Stanford University, Palo Alto, CA, USA, 3Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada, 4Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada, 5Department of Molecular Genetics, University of Toronto, Toronto, Canada, 6Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada and 7Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, CanadaEmail: Danielle Kemmer - dakemmer@interchange.ubc.ca; Lianne M McHardy - liannemarie@gmail.com; Shawn Hoon - shawnh@stanford.edu; Delphine Rebérioux - delphine.reberioux@pierre-fabre.com; Guri Giaever - guri.giaever@utoronto.ca; Corey Nislow - corey.nislow@utoronto.ca; Calvin D Roskelley - roskelly@interchange.ubc.ca; Michel Roberge* - michelr@interchange.ubc.ca* Corresponding author AbstractBackground: Single genome-wide screens for the effect of altered gene dosage on drug sensitivityin the model organism Saccharomyces cerevisiae provide only a partial picture of the mechanism ofaction of a drug.Results: Using the example of the tumor cell invasion inhibitor dihydromotuporamine C, we showthat a more complete picture of drug action can be obtained by combining different chemicalgenomics approaches – analysis of the sensitivity of ρ0 cells lacking mitochondrial DNA, drug-induced haploinsufficiency, suppression of drug sensitivity by gene overexpression and chemical-genetic synthetic lethality screening using strains de…
has type: Article
is shown at: 10.14288/1.0215950
language: eng
peer review status: Reviewed
provider: Vancouver : University of British Columbia Library
publisher: BioMed Central
publisher DOI: 10.1186/1471-2180-9-9
rights: Attribution 4.0 International (CC BY 4.0)
rights URI: http://creativecommons.org/licenses/by/4.0/
scholar level: Faculty
type: Text
identifier URI: http://hdl.handle.net/2429/55185