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

Samar Ali (1) , Emilia Puig Lombardi (2) , Deepanjan Ghosh (3) , Tao Jia (3) , Géraldine Vitry (1) , Lina Saker (1) , Joël Poupon (4) , Marie-Paule Teulade-Fichou (3) , Alain Nicolas (2) , Arturo Londono-Vallejo (2) , Sophie Bombard (3)

1 U1007 - Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives
2 DIG CANCER - Dynamique de l'information génétique : bases fondamentales et cancer
3 CMBC - Chimie et modélisation pour la biologie du cancer
4 Hôpital Lariboisière-Fernand-Widal [APHP]

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. -H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in Gand 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.

Mots clés: G-quadruplex; platinum complexes; telomere dysfunction; DNA damage; ChIP seq; TRF2

Domaines: Cancer; Chimie; Sciences du Vivant [q-bio]

Samar Ali, Emilia Puig Lombardi, Deepanjan Ghosh, Tao Jia, Géraldine Vitry, et al.. Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage. Metallomics, 2021, ⟨10.1093/mtomcs/mfab029⟩. ⟨hal-03326341⟩