A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription.

Howard Hughes Medical Institute, Department of Medicine, School of Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093-0648, USA.
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.
Mesh Terms:
Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, DNA, DNA Damage, DNA Repair, DNA Topoisomerases, Type II, DNA-Binding Proteins, Enzyme Inhibitors, Estradiol, Estrogen Receptor alpha, Histones, Humans, Membrane Proteins, Nucleosomes, Poly(ADP-ribose) Polymerases, Presenilin-2, Promoter Regions, Genetic, Response Elements, Thiobarbiturates, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Transfection
Science Jun. 23, 2006; 312(5781);1798-802 [PUBMED:16794079]
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