title: Doxorubicin enhances nucleosome turnover around promoters.
abstract: Doxorubicin is an anthracycline DNA intercalator that is among the most commonly used anticancer drugs. Doxorubicin causes DNA double-strand breaks in rapidly dividing cells, although whether it also affects general chromatin properties is unknown. Here, we use a metabolic labeling strategy to directly measure nucleosome turnover to examine the effect of doxorubicin on chromatin dynamics in squamous cell carcinoma cell lines derived from genetically defined mice. We find that doxorubicin enhances nucleosome turnover around gene promoters and that turnover correlates with gene expression level. Consistent with a direct action of doxorubicin, enhancement of nucleosome turnover around promoters gradually increases with time of exposure to the drug. Interestingly, enhancement occurs both in wild-type cells and in cells lacking either the p53 tumor suppressor gene or the master regulator of the DNA damage response, ATM, suggesting that doxorubicin action on nucleosome dynamics is independent of the DNA damage checkpoint. In addition, another anthracycline drug, aclarubicin, shows similar effects on enhancing nucleosome turnover around promoters. Our results suggest that anthracycline intercalation promotes nucleosome turnover around promoters by its effect on DNA topology, with possible implications for mechanisms of cell killing during cancer chemotherapy.
authors.affiliation: Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.forename: Steven
authors.initials: S
authors.lastname: Henikoff
mesh_terms: D015250:Aclarubicin / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D051379:Mice; D046228:Microarray Analysis; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D009707:Nucleosomes; D016159:Tumor Suppressor Protein p53; D015250:Aclarubicin; D004317:Doxorubicin; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse