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Nucleic Acids Research 2006 34(6):1900-1911; doi:10.1093/nar/gkl126
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Published online 5 April 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides

Maria Duca1,2,3,4, Dominique Guianvarc'h1,2,3,4, Kahina Oussedik1,2,3,4, Ludovic Halby1,2,3,4, Anna Garbesi5, Daniel Dauzonne6, Claude Monneret6, Neil Osheroff7,8, Carine Giovannangeli1,2,3,4 and Paola B. Arimondo1,2,3,4,*

1 UMR 5153 CNRS Paris, France 2 Muséum National d'Histoire Naturelle USM0503 Paris, France 3 INSERM UR565 Paris, France 4 43 rue Cuvier 75231 Paris cedex 05, France 5 Istituto di Sintesi Organica e Fotoreattività del Consiglio Nazionale delle Ricerche (ISOF-CNR) Via Gobetti 101 40129 Bologna, Italy 6 UMR 176 CNRS, Institut Curie Section de Recherche 26 rue d'Ulm 75248 Paris cedex 05, France 7 Department of Biochemistry, Vanderbilt University School of Medicine Nashville TN 37232-0146, USA 8 Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine Nashville TN 37232-0146, USA

*To whom correspondence should be addressed. Tel: +33 1 40793859; Fax: +33 1 40793705; Email: arimondo{at}mnhn.fr

Received November 24, 2005. Revised December 21, 2005. Accepted March 14, 2006.

Human topoisomerase II (topo II) is the cellular target for a number of widely used antitumor agents, such as etoposide (VP16). These agents ‘poison’ the enzyme and induce it to generate DNA breaks that are lethal to the cell. Topo II-targeted drugs show a limited sequence preference, triggering double-stranded breaks throughout the genome. Circumstantial evidence strongly suggests that some of these breaks induce chromosomal translocations that lead to specific types of leukaemia (called treatment-related or secondary leukaemia). Therefore, efforts are ongoing to decrease these secondary effects. An interesting option is to increase the sequence-specificity of topo II-targeted drugs by attaching them to triplex-forming oligonucleotides (TFO) that bind to DNA in a highly sequence-specific manner. Here five derivatives of VP16 were attached to TFOs. The active topo II poisons, once linked, induced cleavage 13–14 bp from the triplex end where the drug was attached. The use of triple-helical DNA structures offers an efficient strategy for targeting topo II-mediated cleavage to DNA specific sequences. Finally, drug–TFO conjugates are useful tools to investigate the mechanistic details of topo II poisoning.

Present address: Dominique Guianvarc'h, Synthèse, Structure et Fonction de Molécules Bioactives, Université Paris 6, CNRS UMR 7613, 4, place Jussieu, 75005 Paris, France


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