title: Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1.
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.
authors.affiliation: CNRS-UMR, Université Paris Descartes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ourliac-Garnier
authors.forename: Anaïs
authors.initials: A
authors.lastname: Poulet
authors.forename: Razan
authors.initials: R
authors.lastname: Charif
authors.forename: Simon
authors.initials: S
authors.lastname: Amiard
authors.forename: Frédérique
authors.initials: F
authors.lastname: Magdinier
authors.forename: Keyvan
authors.initials: K
authors.lastname: Rezaï
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Giraud-Panis
authors.forename: Sophie
authors.initials: S
authors.lastname: Bombard
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D000089804:Shelterin Complex; D016615:Telomere / Q000737:chemistry* / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*
chemical_list: D000089804:Shelterin Complex; C059329:TERF1 protein, human; C504753:TERF2 protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D004247:DNA; D002945:Cisplatin