Single molecule study of the stability of G-quadruplex DNA as an anti-cancer drug target

In targeted therapy, small molecule drugs are utilized to detect specific targets. G-quadruplex (GQ) structures are such a target for targeted cancer therapy. GQ is a physiologically significant secondary structure of DNA or RNA, which is formed by guanine-rich sequences. Studies on cancer cells show that stabilizing the GQ structures in telomeres with small molecules reduces telomerase activity and proliferation of cancer cells. However, the underlying dynamics of small molecule-GQ interactions are not known. In this study, we performed single molecule measurements to study how stability and dynamics of GQ are impacted by its interactions with several different small molecules. Moreover, we investigated the impact of these molecules on folding dynamics of the GQ structure. We observed significant enhancement in GQ stability in the presence of small molecules, as measured by the fraction of GQ molecules that remained folded against Bloom helicase mediated unfolding at the single molecule level. In addition, our measurements showed that folding of GQ takes place faster than our time resolution over all salt concentrations we studied (2-150 mM KCl) with or without small molecules, making it challenging to identify the impact of small molecules.