title: Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate.
abstract: Homologous recombination is accompanied by extensive changes to chromatin organization at the site of DNA damage. Some of these changes are mediated through acetylation/deacetylation of histones. Here, we show that recombinational repair of DNA damage induced by the anti-cancer drug camptothecin (CPT) and the alkylating agent methyl methanesulfonate (MMS) is blocked by sodium phenylbutyrate (PBA) in the budding yeast Saccharomyces cerevisiae. In particular, PBA suppresses CPT- and MMS-induced genetic recombination as well as DNA double-strand break repair during mating-type interconversion. Treatment with PBA is accompanied by a dramatic reduction in histone H4 lysine 8 acetylation. Live cell imaging of homologous recombination proteins indicates that repair of CPT-induced DNA damage is redirected to a non-recombinogenic pathway in the presence of PBA without loss in cell viability. In contrast, the suppression of MMS-induced recombination by PBA is accompanied by a dramatic loss in cell viability. Taken together, our results demonstrate that PBA inhibits DNA damage-induced homologous recombination likely by mediating changes in chromatin acetylation. Moreover, the combination of PBA with genotoxic agents can lead to different cell fates depending on the type of DNA damage inflicted.
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaloeesvej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Gitte S
authors.initials: GS
authors.lastname: Kaiser
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Germann
authors.forename: Tine
authors.initials: T
authors.lastname: Westergaard
authors.forename: Michael
authors.initials: M
authors.lastname: Lisby
mesh_terms: D000477:Alkylating Agents / Q000037:antagonists & inhibitors; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors; D002166:Camptothecin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004260:DNA Repair; D049770:Genes, Mating Type, Fungal / Q000187:drug effects; D006801:Humans; D008741:Methyl Methanesulfonate / Q000037:antagonists & inhibitors*; D010654:Phenylbutyrates / Q000494:pharmacology*; D051721:Rad52 DNA Repair and Recombination Protein / Q000187:drug effects; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics
chemical_list: D000477:Alkylating Agents; D000972:Antineoplastic Agents, Phytogenic; D010654:Phenylbutyrates; D051721:Rad52 DNA Repair and Recombination Protein; C075773:4-phenylbutyric acid; D008741:Methyl Methanesulfonate; D002166:Camptothecin