title: Influence of nucleotide excision repair on mitoxantrone cytotoxicity.
abstract: Mitoxantrone (MXT) is an anticancer drug structurally related to anthracyclines, such as doxorubicin (DOX). Here we report that cells deficient in nucleotide excision repair (NER) are very sensitive to MXT. However, cells deficient in each of the NER sub-pathways - transcription coupled repair (deficient in CSB protein) and global genome repair (deficient in XPC protein) - demonstrate a difference in sensitivity from each other and also show different responses in cell cycle profile, DNA synthesis and topo II DNA complex formation upon MXT treatment. XPC-deficient cells are slightly more resistant than CSB-deficient cells, and in the same way as MRC5 NER-proficient cells, show G2/M arrest, normal DNA synthesis rate and a pattern of formation of complexes similar to proficient cells, whereas CSB-deficient cells show accumulation in S phase, reduced DNA synthesis and a more intense signal of topo II DNA complexes, indicating that they remain longer in these cells. Complementation of CSB mutant cells with CSB rescue MXT-induced sensitivity and also a decrease in the signal intensity of the complexes, suggest that resolution of these lesions would take place. Taken together, our results indicate that NER proteins are implicated in the response to MXT and that CSB protein has a key role in processing MXT-induced topo II DNA complexes.
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil; Post-Graduation Program in Molecular and Cellular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
authors.forename: Jaqueline Cesar
authors.initials: JC
authors.lastname: Rocha
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil; Post-Graduation Program in Molecular and Cellular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
authors.forename: Franciele Faccio
authors.initials: FF
authors.lastname: Busatto
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil.
authors.forename: Lisiane Knob
authors.initials: LK
authors.lastname: de Souza
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil; Post-Graduation Program in Molecular and Cellular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Electronic address: jenifers@ufcspa.edu.br.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Saffi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D045643:DNA Repair Enzymes / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D000075223:Poly-ADP-Ribose Binding Proteins; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000075223:Poly-ADP-Ribose Binding Proteins; D059005:Topoisomerase II Inhibitors; D004247:DNA; D008942:Mitoxantrone; D004265:DNA Helicases; C078673:ERCC6 protein, human; D004250:DNA Topoisomerases, Type II; D045643:DNA Repair Enzymes
keywords: CSB; Mitoxantrone; Nucleotide excision repair; Topoisomerase II inhibitors; XPC