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Science 312 (5781): 1798-1802

Copyright © 2006 by the American Association for the Advancement of Science

A Topoisomerase IIß-Mediated dsDNA Break Required for Regulated Transcription

Bong-Gun Ju,1 Victoria V. Lunyak,2 Valentina Perissi,1 Ivan Garcia-Bassets,1 David W. Rose,2 Christopher K. Glass,3 Michael G. Rosenfeld1*

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 IIß-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 IIß–dependent dsDNA breaks and the components of the DNA damage and repair machinery 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}

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   Abstract »    Full Text »    PDF »
Dynamic binding of Ku80, Ku70 and NF90 to the IL-2 promoter in vivo in activated T-cells.
L. Shi, D. Qiu, G. Zhao, B. Corthesy, S. Lees-Miller, W. H. Reeves, and P. N. Kao (2007)
Nucleic Acids Res. 35, 2302-2310
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Phosphorylation of Thyroid Hormone Receptor-associated Nuclear Receptor Corepressor Holocomplex by the DNA-dependent Protein Kinase Enhances Its Histone Deacetylase Activity.
M. Jeyakumar, X.-f. Liu, H. Erdjument-Bromage, P. Tempst, and M. K. Bagchi (2007)
J. Biol. Chem. 282, 9312-9322
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Mechanism of Histone H1-Stimulated Glucocorticoid Receptor DNA Binding In Vivo.
S. Belikov, C. Astrand, and O. Wrange (2007)
Mol. Cell. Biol. 27, 2398-2410
   Abstract »    Full Text »    PDF »
In Vitro Fluorescence Anisotropy Analysis of the Interaction of Full-length SRC1a with Estrogen Receptors {alpha} and beta Supports an Active Displacement Model for Coregulator Utilization.
S. Wang, C. Zhang, S. K. Nordeen, and D. J. Shapiro (2007)
J. Biol. Chem. 282, 2765-2775
   Abstract »    Full Text »    PDF »
Bending and breaking the code: dynamic changes in promoter integrity may underlie a new mechanism regulating gene expression.
M. N. Gillespie and G. L. Wilson (2007)
Am J Physiol Lung Cell Mol Physiol 292, L1-L3
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