Antitumour drugs impede DNA uncoiling by topoisomerase I

Daniel A. Koster, Komaraiah Palle, Elisa S. M. Bot, Mary-Ann Bjornsti and Nynke H. Dekker ()
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Daniel A. Koster: Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
Komaraiah Palle: St Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA
Elisa S. M. Bot: Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
Mary-Ann Bjornsti: St Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA
Nynke H. Dekker: Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands

Nature, 2007, vol. 448, issue 7150, 213-217

Abstract: Supercoiled Topoisomerases are enzymes that act to relax supercoiling, a form of built-up strain in DNA. Topoisomerase inhibitors are important antitumour drugs, thought to act by stabilizing a covalent complex between the topoisomerase and DNA, which then sets up a road-block to the DNA replication machinery. The origin of drug efficacy in targeting topoisomerases remains poorly understood, but now a singlemolecule study of the interaction of topotecan, a drug used mainly to treat ovarian cancer and small-cell lung cancer, and a topoisomerase IB–DNA complex, has revealed more details of the process. As illustrated on the cover, positive DNA supercoils accumulate due to the action of the drug (shown red) Such overwinding of the DNA hinders an advancing DNA polymerase and may play a role in the stalling or collapse of a replication fork, ultimately leading to cell death.

Date: 2007
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DOI: 10.1038/nature05938

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