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The G-quadruplex Ligand Telomestatin Inhibits POT1 Binding to Telomeric Sequences In vitro and Induces GFP-POT1 Dissociation from Telomeres in Human Cells

¹ Laboratoire d'Onco-Pharmacologie, JE 2428; ² Centre National de la Recherche Scientifique UMR 6142; ³ Institut Fédératif de Recherche 53, Université de Reims Champagne-Ardenne; ⁴ Institut Jean-Godinot, Reims, France; ⁵ Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique UMR 5161, Ecole Normale Supérieure de Lyon, Lyon, France; and ⁶ Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan

Requests for reprints: Jean-François Riou, Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51096 Reims, France. Phone: 33-3-26-91-80-13; Fax: 33-3-26-91-89-26; E-mail: jf.riou{at}univ-reims.fr.

Telomestatin is a potent G-quadruplex ligand that specifically interacts with the 3' telomeric overhang, leading to its degradation and that induces a delayed senescence and apoptosis of cancer cells. Protection of Telomere 1 (POT1) was recently identified as a specific single-stranded telomere-binding protein involved in telomere capping and T-loop maintenance. We showed here that a telomestatin treatment inhibits POT1 binding to the telomeric overhang in vitro. The treatment of human EcR293 cells by telomestatin induces a dramatic and rapid delocalization of POT1 from its normal telomere sites but does not affect the telomere localization of the double-stranded telomere-binding protein TRF2. Thus, we propose that G-quadruplex stabilization at telomeric G-overhang inactivates POT1 telomeric function, generating a telomere dysfunction in which chromosome ends are no longer properly protected. (Cancer Res 2006; 66(14): 6908-12)

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