title: Effects of an unusual poison identify a lifespan role for Topoisomerase 2 inSaccharomyces cerevisiae.
abstract: A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging inSaccharomyces cerevisiae(yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability. Genetic and biochemical criteria reveal LS1 to be a weak Top2 poison. Top2 poisons induce the accumulation of covalent Top2-linked DNA double strand breaks that, if left unrepaired, lead to genome instability and death. LS1 is toxic to cells deficient in homologous recombination, suggesting that the damage it induces is normally mitigated by genome maintenance systems. The essential roles of yTop2 in proliferating cells may come with a fitness trade-off in older cells that are less able to sense or repair yTop2-mediated DNA damage. Consistent with this idea, cells live longer when yTop2 expression levels are reduced. These results identify intrinsic yTop2-mediated DNA damage as potentially manageable cause of aging.
authors.affiliation: Biology Department, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Tombline
authors.affiliation: Biology Department, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Millen
authors.affiliation: Biology Department, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Polevoda
authors.affiliation: Biology Department, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Matan
authors.initials: M
authors.lastname: Rapaport
authors.affiliation: Biology Department, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Baxter
authors.affiliation: Biology Department, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Van Meter
authors.affiliation: Department of Biopharmaceutical Sciences, UIC College of Pharmacy at Rockford, Rockford, IL 61107, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gilbertson
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham AL, 35205, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Madrey
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham AL, 35205, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham AL, 35205, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Rasmussen
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham AL, 35205, USA.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham AL, 35205, USA.
authors.forename: E Lucile
authors.initials: EL
authors.lastname: White
authors.affiliation: Department of Biopharmaceutical Sciences, UIC College of Pharmacy at Rockford, Rockford, IL 61107, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Nitiss
authors.affiliation: Biology Department, University of Rochester, Rochester, NY 14627, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Goldfarb
mesh_terms: D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D042822:Genomic Instability / Q000187:drug effects; D011042:Poisons / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D011042:Poisons; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: DNA damage; aging; antagonistic pleiotropy; replicative lifespan; topoisomerase 2 poison