Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1 |
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Authors: | Isabelle Ourliac-Garnier Anaïs Poulet Razan Charif Simon Amiard Frédérique Magdinier Keyvan Rezaï Eric Gilson Marie-Josèphe Giraud-Panis Sophie Bombard |
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Institution: | 1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS-UMR8601, Université Paris Descartes, 45 rue des Saints-Pères, 75006, Paris, France 2. Telomeres and Cancer Laboratory, UMR3244, Institut Curie, 26 rue d’Ulm, 75248, Paris, France 3. Université de Lyon, LJC, USR3010 CNRS, Ecole Normale Supérieure de Lyon, 46 allée d’Italie, 69364, Lyon Cedex, France 4. Université de Lyon, LBMC, UMR5239 CNRS, Ecole Normale Supérieure de Lyon, 46 allée d’Italie, 69364, Lyon Cedex, France 5. Laboratoire d’homéostasie cellulaire et cancer, INSERM-UMR-S 1007, Université Paris Descartes, 45 rue des Saints-Pères, 75006, Paris, France 6. Department of Pharmacology Oncology, Centre René Huguenin, Saint-Cloud, France
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Abstract: | Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome
stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat binding factor 2 (TRF2) are the two telomeric proteins
that bind to duplex telomeric DNA through interactions between their C-terminal domain and several guanines of the telomeric
tract. Since the antitumour drug cisplatin binds preferentially to two adjacent guanines, we have investigated whether cisplatin
adducts could affect the binding of TRF1 and TRF2 to telomeric DNA and the property of TRF2 to stimulate telomeric invasion,
a process that is thought to participate in the formation of the t-loop. We show that the binding of TRF1 and TRF2 to telomeric
sequences selectively modified by one GG chelate of cisplatin is markedly affected by cisplatin but that the effect is more
drastic for TRF2 than for TRF1 (3–5-fold more sensitivity for TRF2 than for TRF1). We also report that platinum adducts cause
a decrease in TRF2-dependent stimulation of telomeric invasion in vitro. Finally, in accordance with in vitro data, analysis
of telomeric composition after cisplatin treatment reveals that 60% of TRF2 dissociate from telomeres. |
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