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A Topoisomerase IIß-Mediated dsDNA Break Required for Regulated Transcription
Bong-Gun Ju,1Victoria V. Lunyak,2Valentina Perissi,1Ivan Garcia-Bassets,1David W. Rose,2Christopher K. Glass,3Michael G. Rosenfeld1*
Multiple enzymatic activities are required for transcriptionalinitiation. The enzyme DNA topoisomerase II associates withgene promoter regions and can generate breaks in double-strandedDNA (dsDNA). Therefore, it is of interest to know whether thisenzyme is critical for regulated gene activation. We reportthat the signal-dependent activation of gene transcription bynuclear receptors and other classes of DNA binding transcriptionfactors, including activating protein 1, requires DNA topoisomeraseIIß-dependent, transient, site-specific dsDNA breakformation. Subsequent to the break, poly(adenosine diphosphate–ribose)polymerase–1 enzymatic activity is induced, which is requiredfor a nucleosome-specific histone H1–high-mobility groupB exchange event and for local changes of chromatin architecture.Our data mechanistically link DNA topoisomerase IIß–dependentdsDNA breaks and the components of the DNA damage and repairmachinery in regulated gene transcription.
1 Howard Hughes Medical Institute, Department of Medicine, School of Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093–0648, USA. 2 Department of Medicine, Division of Endocrinology, School of Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093–0648, USA. 3 Department of Cellular and Molecular Medicine, School of Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093–0648, USA.
* To whom correspondence should be addressed. E-mail: mrosenfeld{at}ucsd.edu
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