Predicting the three-dimensional structure of the c-KIT proto-oncogene promoter and the dynamics of its strongly coupled guanine quadruplexes - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Physical Chemistry Letters Année : 2023

Predicting the three-dimensional structure of the c-KIT proto-oncogene promoter and the dynamics of its strongly coupled guanine quadruplexes

Tom Miclot

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-KIT 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.
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Dates et versions

hal-04258965 , version 1 (25-10-2023)

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Emmanuelle Bignon, Angelo Spinello, Tom Miclot, Luisa D’anna, Cosimo Ducani, et al.. Predicting the three-dimensional structure of the c-KIT proto-oncogene promoter and the dynamics of its strongly coupled guanine quadruplexes. Journal of Physical Chemistry Letters, 2023, 14 (20), pp.4704-4710. ⟨10.1021/acs.jpclett.3c00765⟩. ⟨hal-04258965⟩
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