title: Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress.
abstract: 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 sir2Δmutants 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.
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, 5415 Assomption boulevard, Montreal, H1T 2M4, Canada Molecular biology program, Université de Montréal, P.O. Box 6128, Succursale Centre-ville, Montreal, H3C 3J7, Canada.
authors.forename: Antoine
authors.initials: A
authors.lastname: Simoneau
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, 5415 Assomption boulevard, Montreal, H1T 2M4, Canada Molecular biology program, Université de Montréal, P.O. Box 6128, Succursale Centre-ville, Montreal, H3C 3J7, Canada.
authors.forename: Étienne
authors.initials: É
authors.lastname: Ricard
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montreal, H3C 3J7, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Weber
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, 5415 Assomption boulevard, Montreal, H1T 2M4, Canada Molecular biology program, Université de Montréal, P.O. Box 6128, Succursale Centre-ville, Montreal, H3C 3J7, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Hammond-Martel
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, V6T 1Z3, Canada.
authors.forename: Lai Hong
authors.initials: LH
authors.lastname: Wong
authors.affiliation: Infectious Diseases Research Centre-CRI, CHU de Québec Research Center (CHUQ), Université Laval, Québec, G1V 4G2, Canada Department of Microbiology-Infectious Disease and Immunology, Faculty of Medicine, Université Laval, Québec, G1V 0A6, Canada.
authors.forename: Adnane
authors.initials: A
authors.lastname: Sellam
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, V6T 1Z3, Canada.
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, V6T 1Z3, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montreal, H3C 3J7, Canada Department of Biochemistry and Molecular Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, H3C 3J7, Canada martine.raymond@umontreal.ca.
authors.forename: Martine
authors.initials: M
authors.lastname: Raymond
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, 5415 Assomption boulevard, Montreal, H1T 2M4, Canada Department of Medicine, Université de Montréal, Montreal, H3T 1J4, Canada hugo.wurtele@umontreal.ca.
authors.forename: Hugo
authors.initials: H
authors.lastname: Wurtele
mesh_terms: D000107:Acetylation / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D004249:DNA Damage; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D016681:Genome, Fungal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D009536:Niacinamide; D064447:Checkpoint Kinase 2; C067022:RAD53 protein, S cerevisiae; D004706:Endodeoxyribonucleases; C505436:SLX4 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4; C103934:HST1 protein, S cerevisiae; C423033:HST2 protein, S cerevisiae; C512517:Hst3 protein, S cerevisiae; C512518:Hst4 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D006655:Histone Deacetylases