Chromatin determinants impart camptothecin sensitivity

• DOI: 10.15252/embr.201643560
• Publication Date: 2017-04-08T00:10:25Z
• Authors: Fabio Puddu; Israel Salguero; Mareike Herzog; Nicola J Geisler; Vincenzo Costanzo; Stephen P Jackson
• Keywords: DNA Replication; 0303 health sciences; Saccharomyces cerevisiae Proteins; SIR complex; camptothecin; Cell Cycle Proteins; Articles; Naphthols; Saccharomyces cerevisiae; DNA, Ribosomal; Chromatin; DNA-Binding Proteins; H4‐K16; 03 medical and health sciences; DNA Topoisomerases, Type I; Benzamides; Tof1; Humans; Camptothecin; synthetic viability; DNA, Fungal; H4‐K16; SIR complex; Tof1; synthetic viability; Benzamides; Camptothecin; Cell Cycle Proteins; DNA Damage; DNA Replication; DNA Topoisomerases, Type I; DNA, fungal; DNA, Ribosomal; DNA-Binding proteins; humans; Naphthols; saccharomyces cerevisiae; saccharomyces cerevisiae proteins; silent information regulator proteins, saccharomyces cerevisiae; chromatin; Silent Information Regulator Proteins, Saccharomyces cerevisiae; DNA Damage

AbstractCamptothecin‐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 genes SIR1‐4 suppresses much of the hypersensitivity of tof1∆ 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 and tof1∆ 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.