The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

A. Huseinovic, Jolanda van Leeuwen, Tibor van Welsem, Iris Stulemeijer, Fred van Leeuwen, N.P.E. Vermeulen, J.M. Kooter, J.C. Vos

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.
Original languageEnglish
Article numbere0173573
Pages (from-to)1-19
Number of pages19
JournalPLoS ONE
Volume12
Issue number3
DOIs
Publication statusPublished - 14 Mar 2017

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acetaminophen
Acetaminophen
ubiquitin
Ubiquitin
Yeast
Saccharomyces cerevisiae
homeostasis
Homeostasis
toxicity
Toxicity
Genes
genes
liver failure
overdose
hepatotoxicity
DNA-directed RNA polymerase
DNA repair
histones
DNA damage
pharmacokinetics

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Huseinovic, A., van Leeuwen, J., van Welsem, T., Stulemeijer, I., van Leeuwen, F., Vermeulen, N. P. E., ... Vos, J. C. (2017). The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae. PLoS ONE, 12(3), 1-19. [e0173573]. https://doi.org/10.1371/journal.pone.0173573
Huseinovic, A. ; van Leeuwen, Jolanda ; van Welsem, Tibor ; Stulemeijer, Iris ; van Leeuwen, Fred ; Vermeulen, N.P.E. ; Kooter, J.M. ; Vos, J.C. / The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae. In: PLoS ONE. 2017 ; Vol. 12, No. 3. pp. 1-19.
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Huseinovic, A, van Leeuwen, J, van Welsem, T, Stulemeijer, I, van Leeuwen, F, Vermeulen, NPE, Kooter, JM & Vos, JC 2017, 'The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae' PLoS ONE, vol. 12, no. 3, e0173573, pp. 1-19. https://doi.org/10.1371/journal.pone.0173573

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae. / Huseinovic, A.; van Leeuwen, Jolanda; van Welsem, Tibor; Stulemeijer, Iris; van Leeuwen, Fred; Vermeulen, N.P.E.; Kooter, J.M.; Vos, J.C.

In: PLoS ONE, Vol. 12, No. 3, e0173573, 14.03.2017, p. 1-19.

Research output: Contribution to JournalArticleAcademicpeer-review

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AB - Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.

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Huseinovic A, van Leeuwen J, van Welsem T, Stulemeijer I, van Leeuwen F, Vermeulen NPE et al. The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae. PLoS ONE. 2017 Mar 14;12(3):1-19. e0173573. https://doi.org/10.1371/journal.pone.0173573