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Telomerase activity is expressed in approximately 85 % of human cancer cells. The overexpression of telomerase in cancer cells is sufficient enough to maintain the length of telomeres and overcome cellular senescence or apoptosis, which explains the immortal feature of cancer cells. In order to cease the immortality of cancer cells caused by telomerase, a strategy that focuses on the inhibition of telomerase activity has been developed. Due to the feature of G-rich human telomeric sequence (T2AG3 repeats), the telomeres can form a G-quadruplex secondary structure whose steric hindrance may disrupt the telomerase binding. In this project, in order to prevent telomerase from accessing and elongating the telomeres, we investigated the factors that stabilize G-quadruplex structures by using UV-Vis Spectroscopy, Fluorescence Spectroscopy and Surface Plasmon Resonance (SPR). We showed that, among the monovalent cations, potassium maximized the stabilization. The stabilization of DNA G-quadruplex was further enhanced in the presence of ligands such as TmPyP4 and its manganese derivative, Mn(Ⅲ)TmPyP4. We also compared the stability of DNA quadruplex and RNA quadruplex. Interestingly, RNA quadruplex showed greater thermodynamic stability than DNA quadruplex under the same experimental conditions. However, RNA quadruplex was not stabilized by the porphyrin ligands we used. Although the conformation analysis of G-quadruplex and the modeling of G-quadruplex ligands are still under investigation, this project gives an insight into improving the stability of both DNA and RNA quadruplex structures.
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Chiba, Tamaki, "Potential Anticancer Activity via Inhibition of Telomerase Binding: Investigation of Stabilization Factors for G-Quadruplex Structures" (2017). Senior Projects Spring 2017. 42.
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