title: A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription.
abstract: Multiple enzymatic activities are required for transcriptional initiation. The enzyme DNA topoisomerase II associates with gene promoter regions and can generate breaks in double-stranded DNA (dsDNA). Therefore, it is of interest to know whether this enzyme is critical for regulated gene activation. We report that the signal-dependent activation of gene transcription by nuclear receptors and other classes of DNA binding transcription factors, including activating protein 1, requires DNA topoisomerase IIbeta-dependent, transient, site-specific dsDNA break formation. Subsequent to the break, poly(adenosine diphosphate-ribose) polymerase-1 enzymatic activity is induced, which is required for a nucleosome-specific histone H1-high-mobility group B exchange event and for local changes of chromatin architecture. Our data mechanistically link DNA topoisomerase IIbeta-dependent dsDNA breaks and the components of the DNA damage and repair machinery in regulated gene transcription.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, School of Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0648, USA.
authors.forename: Bong-Gun
authors.initials: BG
authors.lastname: Ju
authors.forename: Victoria V
authors.initials: VV
authors.lastname: Lunyak
authors.forename: Valentina
authors.initials: V
authors.lastname: Perissi
authors.forename: Ivan
authors.initials: I
authors.lastname: Garcia-Bassets
authors.forename: David W
authors.initials: DW
authors.lastname: Rose
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009707:Nucleosomes / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D053766:Presenilin-2; D011401:Promoter Regions, Genetic; D020218:Response Elements; D013858:Thiobarbiturates / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D006657:Histones; D008565:Membrane Proteins; D009707:Nucleosomes; C508861:PSEN2 protein, human; D053766:Presenilin-2; D013858:Thiobarbiturates; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D004958:Estradiol; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D004250:DNA Topoisomerases, Type II; C045459:merbarone