Predicting the Three-Dimensional Structure of the c- Proto-Oncogene Promoter and the Dynamics of Its Strongly Coupled Guanine Quadruplexes.
Fiche publication
Date publication
mai 2023
Journal
The journal of physical chemistry letters
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GRANDEMANGE Stéphanie
Tous les auteurs :
Bignon E, Spinello A, Miclot T, D'Anna L, Ducani C, Grandemange S, Barone G, Monari A, Terenzi A
Lien Pubmed
Résumé
Guanine quadruplexes (G4s) play essential protective and regulatory roles within cells, influencing gene expression. In several gene-promoter regions, multiple G4-forming sequences are in close proximity and may form three-dimensional arrangements. We analyze the interplay among the three neighboring G4s in the c- proto-oncogene promoter (WK1, WSP, and WK2). We highlight that the three G4s are structurally linked and their cross-talk favors the formation of a parallel structure for WSP. Relying on all-atom molecular dynamic simulations exceeding the μs time scale and using enhanced sampling methods, we provide the first computationally resolved structure of a well-organized G4 cluster in the promoter of a crucial gene involved in cancer development. Our results indicate that neighboring G4s influence their mutual three-dimensional arrangement and provide a powerful tool to predict and interpret complex DNA structures that can ultimately be used as a starting point for drug discovery.
Référence
J Phys Chem Lett. 2023 05 12;:4704-4710