AFFINITY AND SELECTIVITY OF AZACYANINES TO G-QUADRUPLEX FORMING PROMOTER REGIONS

2022-2-9
Kırmacı, Fahriye Nur
DNA has multiple levels of regulations owing to complex regulatory units. Promoters are among the most crucial regulatory sequence units in DNA, altering transcription initiation. Recent studies have shown that secondary structures called G-quadruplexes (G4s) can be found in promoter regions of certain genes along with the common double-helical Watson-Crick DNA. G-quadruplexes are four-stranded helical structures formed by the π-π stacking of G-tetrad structures with a pattern called G-tracts. New findings suggest that these noncanonical structures are transcriptionally altering the expression of critical proteins in healthy cells and possibly involved in the formation of cancerous tissue. For this reason, the promoter regions that have the capacity to form G-quadruplex structures have become the target of many drug development efforts against cancer. Within the scope of this thesis, it is revealed that five Azacyanine derivatives (Azamethyl, Aza4, Aza5, Azabutyl, and Azaisobutyl) were preferentially binding to the c-MYC (Cellular Myelocytomatosis) promoter region over the G4 forming promoter regions of B-Cell CLL/lymphoma 2 (BCL-2), Vascular Endothelial Growth Factor (VEGF), Kirsten Rat Sarcoma (KRAS), Human Epidermal Growth Factor Receptor 2 (HER-2) and Retinoblastoma (RB) via competition dialysis. Interactions of G4 c-MYC and Azamethyl were investigated further using UV-Vis, Fluorescence, and Circular Dichroism spectroscopy. G4 of c-MYC promoter region was found to be stabilized by Azamethyl via thermal denaturation studies. Thermal denaturation temperature of c-MYC was shifted up to 20°C with varying Azamethyl concentration. Lastly, fluorescence spectroscopy unveiled the association constant between c-MYC and Azamethyl as 2.9 x 105 ±1.4 x 104 M-1.

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Citation Formats
F. N. Kırmacı, “AFFINITY AND SELECTIVITY OF AZACYANINES TO G-QUADRUPLEX FORMING PROMOTER REGIONS,” M.S. - Master of Science, Middle East Technical University, 2022.