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J. Biol. Chem., Vol. 281, Issue 50, 38721-38729, December 15, 2006

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Telomestatin-induced Telomere Uncapping Is Modulated by POT1 through G-overhang Extension in HT1080 Human Tumor Cells^*

Dennis Gomez¹, Thomas Wenner¹², Bertrand Brassart¹, Céline Douarre¹³, Marie-Françoise O'Donohue, Victoria El Khoury, Kazuo Shin-ya^¶, Hamid Morjani, Chantal Trentesaux, and Jean-François Riou⁴

From the Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51 Rue Cognacq-Jay, 51096 Reims, France, UMR CNRS 6142, Reims, France, and ^¶Institute of Molecular and Cellular Biosciences, the University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan

Telomestatin is a potent G-quadruplex ligand that interacts with the 3' telomeric overhang, leading to its degradation, and induces a delayed senescence and apoptosis of cancer cells. POT1 and TRF2 were recently identified as specific telomere-binding proteins involved in telomere capping and t-loop maintenance and whose interaction with telomeres is modulated by telomestatin. We show here that the treatment of HT1080 human tumor cells by telomestatin induces a rapid decrease of the telomeric G-overhang and of the double-stranded telomeric repeats. Telomestatin treatment also provokes a strong decrease of POT1 and TRF2 from their telomere sites, suggesting that the ligand triggers the uncapping of the telomere ends. The effect of the ligand is associated with an increase of the -H2AX foci, one part of them colocalizing at telomeres, thus indicating the occurrence of a DNA damage response at the telomere, but also the presence of additional DNA targets for telomestatin. Interestingly, the expression of GFP-POT1 in HT1080 cells increases both telomere and G-overhang length. As compared with HT1080 cells, HT1080GFP-POT1 cells presented a resistance to telomestatin treatment characterized by a protection to the telomestatin-induced growth inhibition and the G-overhang shortening. This protection is related to the initial G-overhang length rather than to its degradation rate and is overcome by increased telomestatin concentration. Altogether these results suggest that telomestatin induced a telomere dysfunction in which G-overhang length and POT1 level are important factors but also suggest the presence of additional DNA sites of action for the ligand.

Received for publication, June 19, 2006 , and in revised form, October 16, 2006.

^* This work was supported in part by the "Association pour la Recherche Contre le Cancer" Grant 3644 and by the "Ligue Nationale Contre le Cancer, Equipe Labelisée 2006 (to 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S8.

¹ These authors contributed equally to this work.

² Supported by a postdoctoral fellowship granted by the "Région Champagne-Ardenne."

³ Supported by a doctoral fellowship granted by the "Association pour la Recherche Contre le Cancer."

⁴ To whom correspondence should be addressed. Tel.: 33-3-26-91-80-13; Fax: 33-3-26-91-89-26; E-mail: jean-francois.riou{at}univ-reims.fr.

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