title: Chromatin determinants impart camptothecin sensitivity.
abstract: Camptothecin-induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genesSIR1-4suppresses much of the hypersensitivity oftof1∆strains towards this agent. We show that disruption of rDNA or telomeric silencing does not mediate camptothecin resistance but that disruption of Sir1-dependent chromatin domains is sufficient to suppress camptothecin sensitivity in wild-type andtof1∆cells. We suggest that topoisomerase 1 inhibition in proximity of these domains causes topological stress that leads to DNA hypercatenation, especially in the absence of the Tof1/Csm3 complex. Finally, we provide evidence of the evolutionarily conservation of this mechanism.
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK f.puddu@gurdon.cam.ac.uk s.jackson@gurdon.cam.ac.uk.
authors.forename: Fabio
authors.identifier: 0000-0002-2033-5209
authors.initials: F
authors.lastname: Puddu
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Israel
authors.initials: I
authors.lastname: Salguero
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.|The Wellcome Trust Sanger Institute, Hinxton Cambridge, UK.
authors.forename: Mareike
authors.initials: M
authors.lastname: Herzog
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Geisler
authors.affiliation: IFOM (Fondazione Istituto FIRC di Oncologia Molecolare), Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Costanzo
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK f.puddu@gurdon.cam.ac.uk s.jackson@gurdon.cam.ac.uk.
authors.forename: Stephen P
authors.identifier: 0000-0001-9317-7937
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D002166:Camptothecin / Q000378:metabolism / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002843:Chromatin; D004249:DNA Damage; D004261:DNA Replication; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004271:DNA, Fungal / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009284:Naphthols / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D018797:Cell Cycle Proteins; D002843:Chromatin; D004271:DNA, Fungal; D004275:DNA, Ribosomal; D004268:DNA-Binding Proteins; D009284:Naphthols; C084121:SIR1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C119636:TOF1 protein, S cerevisiae; C439060:sirtinol; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin
keywords: H4‐K16; SIR complex; Tof1; camptothecin; synthetic viability