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First published on December 29, 2004; DOI: 10.1124/mol.104.007633

0026-895X/05/6704-1186-1194$20.00
Mol Pharmacol 67:1186-1194, 2005

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Original Article

Selective Inhibition of Topoisomerase I and Various Steps of Spliceosome Assembly by Diospyrin Derivatives

Jamal Tazi, Nadia Bakkour, Johann Soret, Latifa Zekri, Banasri Hazra, William Laine, Brigitte Baldeyrou, Amélie Lansiaux, and Christian Bailly

IGM-Centre National de la Recherche Scientifique-UMII, Unité Mixte Recherche 5535, l'Institut Fédératif de Recherches 122, Montpellier, France (J.T., N.B., J.S., L.Z.); Department of Pharmaceutical Technology, Jadavpur University, Calcutta, India (B.H.); and Institut National de la Santé et de la Recherche Médicale UR-524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Lille, France (W.L., B.B., A.L., C.B.)

Abstract

Pre-mRNA splicing is an essential step of the expression of most metazoan protein-coding genes, which is often regulated in a cell type-specific or developmental manner. We have demonstrated previously that human DNA topoisomerase I, an extensively studied target for anticancer drugs, also has an intrinsic protein kinase activity that specifically phosphorylates proteins involved in splice site selection. Therefore, DNA topoisomerase I was recently shown to play a critical role in alternative splicing. Here, we have exploited these novel properties of DNA topoisomerase I to develop entirely novel diospyrin derivatives targeting its protein kinase activity and thereby modulating pre-mRNA splicing. Although some derivatives indeed inhibit kinase activity of topoisomerase I, they did not block reactions of topoisomerase I on DNA. However, these drugs interfere with camptothecin-dependent topoisomerase I-mediated DNA cleavage, implying that diospyrin derivatives mediate a conformational change of topoisomerase I. It is note-worthy that in vitro splicing reactions revealed that diospyrin derivatives alter various steps of splicing. Some diospyrin derivatives inhibit either the first or the second catalytic step of splicing but not spliceosome assembly, whereas diospyrin itself prevents the formation of full spliceosome. Our data revealed for the first time that diospyrin derivatives are able to stall the dynamic assembly of the spliceosome and open the exciting possibility of using these derivatives to correct aberrant splicing in human genetic diseases.

Received September 25, 2004; accepted December 20, 2004

Address correspondence to: Dr. C. Bailly, IRCL, Place de Verdun, Lille, France. E-mail: bailly{at}lille.inserm.fr






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