title: ATP-dependent chromatin remodeling and histone acetyltransferases in 5-FU cytotoxicity in Saccharomyces cerevisiae.
abstract: Chromatin is thought to modulate access of repair proteins to DNA lesions, and may be altered by chromatin remodelers to facilitate repair. We investigated the participation of chromatin remodelers and DNA repair in 5-fluorouracil (5-FU) cytotoxicity in Saccharomyces cerevisiae. 5-FU is an antineoplastic drug commonly used in clinical settings. Among the several strains tested, only those with deficiencies in ATP-dependent chromatin remodeling (CR) and some histone acetyltransferases (HAT) exhibited sensitivity to 5-FU. CR and HAT double-mutants exhibited increased resistance to 5-FU in comparison to the wild-type mutant, but were still arrested in G2/M, as were the sensitive strains. The participation of Htz1p in 5-FU toxicity was also evaluated in single- and double-mutants of CR and HAT; the most significant effect was on cell cycle distribution. 5-FU lesions are repaired by different DNA repair machineries, including homologous recombination (HR) and post-replication repair (PRR). We investigated the role of CR and HAT in these DNA repair pathways. Deficiencies in Nhp10 and CR combined with deficiencies in HR or PRR increased 5-FU sensitivity; however, combined deficiencies of HAT, HR, and PRR did not. CRs are directly recruited to DNA damage and lead to chromatin relaxation, which facilitates access of HR and PRR proteins to 5-FU lesions. Combined deficiencies in HAT with defects in HR and PRR did not potentiate 5-FU cytotoxicity, possibly because they function in a common pathway.
authors: Centro de Biotecnologia, Departamento de Biofísica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
authors: R
authors: R
authors: Matuo
authors: F G
authors: FG
authors: Sousa
authors: D
authors: D
authors: Bonatto
authors: A A
authors: AA
authors: Mielniczki-Pereira
authors: J
authors: J
authors: Saffi
authors: D G
authors: DG
authors: Soares
authors: A E
authors: AE
authors: Escargueil
authors: A K
authors: AK
authors: Larsen
authors: J A P
authors: JA
authors: Henriques
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004260:DNA Repair; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000378:metabolism / Q000633:toxicity*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D059765:Homologous Recombination; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D004271:DNA, Fungal; D000255:Adenosine Triphosphate; D051548:Histone Acetyltransferases; D005472:Fluorouracil