Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine

Angelina Huseinovic, Marc van Dijk, Nico P E Vermeulen, Fred van Leeuwen, Jan M Kooter, J Chris Vos

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin-related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action.

LanguageEnglish
Pages259-268
Number of pages10
JournalToxicology in Vitro
Volume47
Early online date16 Dec 2017
DOIs
StatePublished - Mar 2018

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Acetaminophen
Drug-Related Side Effects and Adverse Reactions
Yeast
Toxicity
Saccharomyces cerevisiae
Tyrosine
Pharmaceutical Preparations
Yeasts
Ubiquitin
Genes
Amino Acids
Stereoisomerism
Quinine
Deubiquitinating Enzymes
Ibuprofen
Peroxides
Cluster analysis
Sirolimus
Cycloheximide
Post Translational Protein Processing

Keywords

  • Journal Article

Cite this

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title = "Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine",
abstract = "Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin-related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action.",
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author = "Angelina Huseinovic and {van Dijk}, Marc and Vermeulen, {Nico P E} and {van Leeuwen}, Fred and Kooter, {Jan M} and Vos, {J Chris}",
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Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine. / Huseinovic, Angelina; van Dijk, Marc; Vermeulen, Nico P E; van Leeuwen, Fred; Kooter, Jan M; Vos, J Chris.

In: Toxicology in Vitro, Vol. 47, 03.2018, p. 259-268.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine

AU - Huseinovic,Angelina

AU - van Dijk,Marc

AU - Vermeulen,Nico P E

AU - van Leeuwen,Fred

AU - Kooter,Jan M

AU - Vos,J Chris

N1 - Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

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N2 - Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin-related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action.

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