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J. Biol. Chem., Vol. 279, Issue 21, 21873-21882, May 21, 2004

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Distinct Effects of Topoisomerase I and RNA Polymerase I Inhibitors Suggest a Dual Mechanism of Nucleolar/Nucleoplasmic Partitioning of Topoisomerase I^*

Morten O. Christensen, René M. Krokowski, Hans U. Barthelmes, Robert Hock, Fritz Boege, and Christian Mielke¶

From the Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University, Medical School, Moorenstrasse 5, D-40225 Duesseldorf and the Department of Cell and Developmental Biology, Biocenter, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany

Topoisomerase I is mostly nucleolar, because it plays a preeminent role in ribosomal DNA (rDNA) transcription. It is cleared from nucleoli following exposure to drugs stabilizing covalent DNA intermediates of the enzyme (e.g. camptothecin) or inhibiting RNA polymerases (e.g. actinomycin D), an effect summarily attributed to blockade of rDNA transcription. Here we show that two distinct mechanisms are at work: (i) Both drugs induce inactivation and segregation of the rRNA transcription machinery. With actinomycin D this leads to a co-migration of RNA-polymerase I and topoisomerase I to the nucleolar perimeter. The process has a slow onset (>20 min), is independent of topoisomerase I activity, but requires the N-terminal domain of the enzyme to colocalize with RNA polymerase I. (ii) Camptothecin induces, in addition, immobilization of active topoisomerase I on genomic DNA resulting in rapid nucleolar clearance and spreading of the enzyme to the entire nucleoplasm. This effect is independent of the state of rRNA transcription, involves segregation of topoisomerase I from RNA polymerase I, has a rapid onset (<1 min), and requires catalytic activity but neither the N-terminal domain of topoisomerase I nor its major sumoylation site. Thus, nucleolar/nucleoplasmic partitioning of topoisomerase I is regulated by interactions with RNA polymerase I and DNA but not by sumoylation.

Received for publication, January 16, 2004 , and in revised form, February 27, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft (Grants Bo 910/3-1, Bo 910/3-2, Bo 910/4-1, Bo 910/5-1, GRK 639, and GRK 1033) is acknowledged. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 49-211-811-9323; Fax: 49-211-811-8021; E-mail: christian.mielke{at}med.uni-duesseldorf.de.

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