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Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress

The Saccharomyces cerevisiae genome encodes five sirtuins (Sir2 and Hst1–4), which constitute a conserved family of NAD-dependent histone deacetylases. Cells lacking any individual sirtuin display mild growth and gene silencing defects. However, hst3Δ hst4Δ double mutants are exquisitely sensitive t...

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Autores principales: Simoneau, Antoine, Ricard, Étienne, Weber, Sandra, Hammond-Martel, Ian, Wong, Lai Hong, Sellam, Adnane, Giaever, Guri, Nislow, Corey, Raymond, Martine, Wurtele, Hugo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824096/
https://www.ncbi.nlm.nih.gov/pubmed/26748095
http://dx.doi.org/10.1093/nar/gkv1537
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author Simoneau, Antoine
Ricard, Étienne
Weber, Sandra
Hammond-Martel, Ian
Wong, Lai Hong
Sellam, Adnane
Giaever, Guri
Nislow, Corey
Raymond, Martine
Wurtele, Hugo
author_facet Simoneau, Antoine
Ricard, Étienne
Weber, Sandra
Hammond-Martel, Ian
Wong, Lai Hong
Sellam, Adnane
Giaever, Guri
Nislow, Corey
Raymond, Martine
Wurtele, Hugo
author_sort Simoneau, Antoine
collection PubMed
description The Saccharomyces cerevisiae genome encodes five sirtuins (Sir2 and Hst1–4), which constitute a conserved family of NAD-dependent histone deacetylases. Cells lacking any individual sirtuin display mild growth and gene silencing defects. However, hst3Δ hst4Δ double mutants are exquisitely sensitive to genotoxins, and hst3Δ hst4Δ sir2Δ mutants are inviable. Our published data also indicate that pharmacological inhibition of sirtuins prevents growth of several fungal pathogens, although the biological basis is unclear. Here, we present genome-wide fitness assays conducted with nicotinamide (NAM), a pan-sirtuin inhibitor. Our data indicate that NAM treatment causes yeast to solicit specific DNA damage response pathways for survival, and that NAM-induced growth defects are mainly attributable to inhibition of Hst3 and Hst4 and consequent elevation of histone H3 lysine 56 acetylation (H3K56ac). Our results further reveal that in the presence of constitutive H3K56ac, the Slx4 scaffolding protein and PP4 phosphatase complex play essential roles in preventing hyperactivation of the DNA damage-response kinase Rad53 in response to spontaneous DNA damage caused by reactive oxygen species. Overall, our data support the concept that chromosome-wide histone deacetylation by sirtuins is critical to mitigate growth defects caused by endogenous genotoxins.
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spelling pubmed-48240962016-04-08 Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress Simoneau, Antoine Ricard, Étienne Weber, Sandra Hammond-Martel, Ian Wong, Lai Hong Sellam, Adnane Giaever, Guri Nislow, Corey Raymond, Martine Wurtele, Hugo Nucleic Acids Res Genome Integrity, Repair and Replication The Saccharomyces cerevisiae genome encodes five sirtuins (Sir2 and Hst1–4), which constitute a conserved family of NAD-dependent histone deacetylases. Cells lacking any individual sirtuin display mild growth and gene silencing defects. However, hst3Δ hst4Δ double mutants are exquisitely sensitive to genotoxins, and hst3Δ hst4Δ sir2Δ mutants are inviable. Our published data also indicate that pharmacological inhibition of sirtuins prevents growth of several fungal pathogens, although the biological basis is unclear. Here, we present genome-wide fitness assays conducted with nicotinamide (NAM), a pan-sirtuin inhibitor. Our data indicate that NAM treatment causes yeast to solicit specific DNA damage response pathways for survival, and that NAM-induced growth defects are mainly attributable to inhibition of Hst3 and Hst4 and consequent elevation of histone H3 lysine 56 acetylation (H3K56ac). Our results further reveal that in the presence of constitutive H3K56ac, the Slx4 scaffolding protein and PP4 phosphatase complex play essential roles in preventing hyperactivation of the DNA damage-response kinase Rad53 in response to spontaneous DNA damage caused by reactive oxygen species. Overall, our data support the concept that chromosome-wide histone deacetylation by sirtuins is critical to mitigate growth defects caused by endogenous genotoxins. Oxford University Press 2016-04-07 2016-01-08 /pmc/articles/PMC4824096/ /pubmed/26748095 http://dx.doi.org/10.1093/nar/gkv1537 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Simoneau, Antoine
Ricard, Étienne
Weber, Sandra
Hammond-Martel, Ian
Wong, Lai Hong
Sellam, Adnane
Giaever, Guri
Nislow, Corey
Raymond, Martine
Wurtele, Hugo
Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress
title Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress
title_full Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress
title_fullStr Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress
title_full_unstemmed Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress
title_short Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress
title_sort chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of dna damage-induced signaling upon replicative stress
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824096/
https://www.ncbi.nlm.nih.gov/pubmed/26748095
http://dx.doi.org/10.1093/nar/gkv1537
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