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Nucleic Acids Research 2004 32(17):5163-5173; doi:10.1093/nar/gkh847
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Published online 4 October 2004

Nucleic Acids Research, Vol. 32 No. 17 © Oxford University Press 2004; all rights reserved

Position- and orientation-specific enhancement of topoisomerase I cleavage complexes by triplex DNA structures

Smitha Antony, Paola B. Arimondo1, Jian-Sheng Sun1 and Yves Pommier*

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA and 1 USM 0503 Muséum National d'Histoire Naturelle, UMR 5153 CNRS-MNHN, INSERM U565, 43 rue Cuvier, BP26, 75231 Paris cedex 05, France

* To whom correspondence should be addressed at Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Building 37, Room 5068, National Institutes of Health, Bethesda, MD 20892-4255, USA. Tel: +1 301 496 5944; Fax: +1 301 402 0752; Email: pommier{at}nih.gov

Received May 8, 2004; Revised July 27, 2004; Accepted September 7, 2004

Topoisomerase I (Top1) activities are sensitive to various endogenous base modifications, and anticancer drugs including the natural alkaloid camptothecin. Here, we show that triple helix-forming oligonucleotides (TFOs) can enhance Top1-mediated DNA cleavage by affecting either or both the nicking and the closing activities of Top1 depending on the position and the orientation of the triplex DNA structure relative to the Top1 site. TFO binding 1 bp downstream from the Top1 site enhances cleavage by inhibiting religation and to a lesser extent DNA nicking. In contrast, TFO binding 4 bp downstream from the Top1 site enhances DNA nicking especially when the 3' end of the TFO is proximal to the Top1 site. However, when the orientation of the triplex is inverted, with its 5' terminus 4 bp downstream from the Top1 site, religation is also inhibited. These position- and orientation-dependent effects of triplex structures on the Top1-mediated DNA cleavage and religation are discussed in the context of molecular modeling and effects of TFO on DNA twist and mobility at the duplex/triplex junction.


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