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J. Biol. Chem., Vol. 279, Issue 40, 41487-41494, October 1, 2004

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Interaction of Telomestatin with the Telomeric Single-strand Overhang^*

Dennis Gomez, Rajaa Paterski, Thibault Lemarteleur, Kazuo Shin-ya, Jean-Louis Mergny¶, and Jean-François Riou||

From the Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne Ardenne, 51 rue Cognacq-Jay, 51096 Reims, France, the Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan, and the ^¶Laboratoire de Biophysique, Muséum National d'Histoire Naturelle USM 503, INSERM Unité 565, CNRS UMR 5153, 43 rue Cuvier, 75005 Paris, France

The extremities of chromosomes end in a G-rich single-stranded overhang that has been implicated in the onset of the replicative senescence. The repeated sequence forming a G-overhang is able to adopt a peculiar four-stranded DNA structure in vitro called a G-quadruplex, which is a poor substrate for telomerase. Small molecule ligands that selectively stabilize the telomeric G-quadruplex induce telomere shortening and a delayed growth arrest. Here we show that the G-quadruplex ligand telomestatin has a dramatic effect on the conformation of intracellular G-overhangs. Competition experiments indicate that telomestatin strongly binds in vitro and in vivo to the telomeric overhang and impairs its single-stranded conformation. Long-term treatment of cells with telomestatin greatly reduces the G-overhang size, as evidenced by specific hybridization or telomeric oligonucleotide ligation assay experiments, with a concomitant delayed loss of cell viability. In vivo protection experiments using dimethyl sulfate also indicate that telomestatin treatment alters the dimethyl sulfate effect on G-overhangs, a result compatible with the formation of a local quadruplex structure at telomeric overhang. Altogether these experiments strongly support the hypothesis that the telomeric G-overhang is an intracellular target for the action of telomestatin.

Received for publication, June 2, 2004 , and in revised form, July 21, 2004.

^* This work was supported by Association pour la Recherche contre le Cancer Grants 4321 and 3365 (to J.-L. M.) and 4691 (to J.-F. R.) and an Action Concertée Incitative "Médicament et Cibles thérapeutiques" from the Ministère de la Recherche et de la Technologie (to J.-L. M. and J.-F. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: JE 2428 Onco-Pharmacologie, UFR de Pharmacie, 51 rue Cognacq-Jay, 51096 Reims, France. E-mail: jf.riou{at}univ-reims.fr.

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