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Nucleic Acids Research, 2003, Vol. 31, No. 14 4031-4040
© 2003 Oxford University Press

Spatial organization of topoisomerase I-mediated DNA cleavage induced by camptothecin–oligonucleotide conjugates

Paola B. Arimondo*, Stéphane Angenault1, Ludovic Halby, Alexandre Boutorine, Frédéric Schmidt1, Claude Monneret1, Thérèse Garestier, Jian-Sheng Sun, Christian Bailly2 and Claude Hélène

Laboratoire de Biophysique, USM0503 Muséum National d’Histoire Naturelle, UMR8646 CNRS, UR565 INSERM, 43 Rue Cuvier, 75231 Paris Cedex 05, France, 1 Laboratoire de Pharmacochimie, UMR176 CNRS, Institut Curie, Section Recherche, 26 Rue d’Ulm, 75248 Paris Cedex 05, France and 2 INSERM UR524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place Verdun, 59045 Lille, France

*To whom correspondence should be addressed. Tel: +33 1 40793859; Fax: +33 1 40793705; Email: arimondo{at}mnhn.fr
This paper is dedicated to the memory of Prof. Claude Hélène

Triple helix-forming oligonucleotides covalently linked to topoisomerase I inhibitors, in particular the antitumor agent camptothecin, trigger topoisomerase I-mediated DNA cleavage selectively in the proximity of the binding site of the oligonucleotide vector. In the present study, we have performed a systematic analysis of the DNA cleavage efficiency as a function of the positioning of the camptothecin derivative, either on the 3' or the 5' side of the triplex, and the location of the cleavage site. A previously identified cleavage site was inserted at different positions within two triplex site-containing 59 bp duplexes. Sequence-specific DNA cleavage by topoisomerase I occurs only with triplex conjugates bearing the inhibitor at the 3'-end of the oligonucleotide and on the oligopyrimidine strand of the duplex. The lack of targeted cleavage on the 5' side is attributed to the structural differences of the 3' and 5' duplex–triplex DNA junctions. The changes induced in the double helix by the triple-helical structure interfere with the action of the enzyme according to a preferred spatial organization. Camptothecin conjugates of oligonucleotides provide efficient tools to probe the organization of the topoisomerase I–DNA complex and will be useful to understand the functioning of topoisomerase I in living cells.


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