Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage

• Published in: Metallomics 2021-06, Vol.13 (6)
• Main Authors: Ali, Samar, Lombardi, Emilia Puig, Ghosh, Deepanjan, Jia, Tao, Vitry, Géraldine, Saker, Lina, Poupon, Joël, Teulade-Fichou, Marie-Paule, Nicolas, Alain, Londono-Vallejo, Arturo, Bombard, Sophie
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Cancer; Cell Proliferation; Chemical Sciences; Cisplatin - pharmacology; DNA Damage; Female; G-Quadruplexes; Humans; Life Sciences; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Telomere - drug effects; Telomeric Repeat Binding Protein 2 - genetics; Telomeric Repeat Binding Protein 2 - metabolism; Tumor Cells, Cultured
• ISSN: 1756-591X; 1756-5901; 1756-591X
• DOI: 10.1093/mtomcs/mfab029

Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. γ-H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.