A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription.
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.
Ju
Bong-Gun
BG
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0648, USA.
Lunyak
Victoria V
VV
Perissi
Valentina
V
Garcia-Bassets
Ivan
I
Rose
David W
DW
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
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
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