NMR And Biophysical Studies Of G-Quadruplex DNA Within The KRAS Proto-Oncogene Promoter Region
European Biophysics Journal
The role of G-quadruplexes (G4) which can coexist with canonical duplex DNA in the human genome is still largely unknown. Although G4s are found throughout the entire genome, much of the attention have been invested in promotor regions of disease-related genes. The human KRAS proto-oncogene contains a nuclease hypersensitive element (4) located upstream of the major transcription start site. This region regulates transcription of KRAS and it was proposed as a new target for drug development. The knowledge of the detailed structure of this target is crucial for the development of new effective drugs. In this study, we report a high-resolution NMR structure of the G-rich element within the KRAS NHE, and their interaction with small ligands. The G-rich elements forms a parallel structure with three G-quartets connected by a four-nucleotide loop, two one-nucleotide double-chain-reversal loops and a thymine bulge. The loops of different lengths and the presence of a bulge between G-quartets are structural elements that can potentially be targeted by small ligands that would further stabilize the structure. In addition, we explore the polymorphism of G-quadruplexes structures within the promotor region. Consequently, our work suggests an alternative route for the development of anticancer agents that could regulate KRAS expression.
G. F. Salgado, J. Marquevielle, P. Notelet, Liliya A. Yatsunyk, A. Guedin, A. Kerkour, and J.-L. Mergny.
"NMR And Biophysical Studies Of G-Quadruplex DNA Within The KRAS Proto-Oncogene Promoter Region".
European Biophysics Journal.
Issue Supplement 1.