title: Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases.
abstract: Nicotinamide is both a reaction product and an inhibitor of the conserved sirtuin family of deacetylases, which have been implicated in a broad range of cellular functions in eukaryotes from yeast to humans. Phenotypes observed following treatment with nicotinamide are most often assumed to stem from inhibition of one or more of these enzymes. Here, we used this small molecule to inhibit multiple sirtuins at once during treatment with DNA damaging agents in the Saccharomyces cerevisiae model system. Since sirtuins have been previously implicated in the DNA damage response, we were surprised to observe that nicotinamide actually increased the survival of yeast cells exposed to the DNA damage agent MMS. Remarkably, we found that enhanced resistance to MMS in the presence of nicotinamide was independent of all five yeast sirtuins. Enhanced resistance was also independent of the nicotinamide salvage pathway, which uses nicotinamide as a substrate to generate NAD+, and of a DNA damage-induced increase in the salvage enzyme Pnc1 Our data suggest a novel and unexpected function for nicotinamide that has broad implications for its use in the study of sirtuin biology across model systems.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8M5, Canada Ottawa Institute of Systems Biology, University of Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rössl
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8M5, Canada Ottawa Institute of Systems Biology, University of Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Bentley-DeSousa
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8M5, Canada Ottawa Institute of Systems Biology, University of Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Tseng
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8M5, Canada Ottawa Institute of Systems Biology, University of Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Nwosu
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8M5, Canada Ottawa Institute of Systems Biology, University of Ottawa, Ontario K1H 8M5, Canada mdowne2@uottawa.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Downey
mesh_terms: D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D020868:Gene Silencing; D056545:Group III Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D008741:Methyl Methanesulfonate / Q000633:toxicity; D009536:Niacinamide / Q000494:pharmacology; D009535:Nicotinamidase / Q000235:genetics*; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D037761:Sirtuins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D009536:Niacinamide; D008741:Methyl Methanesulfonate; D056545:Group III Histone Deacetylases; D037761:Sirtuins; D009535:Nicotinamidase; C474330:PNC1 protein, S cerevisiae
keywords: DNA damage; NAD+; Pnc1; checkpoint; nicotinamide; sirtuins