Structural studies of nucleic acids : dynamics of RNA pseudoknots and G-quadruplex DNA-ligand interactions

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Date

2001-12

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Rangan, Anupama

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Abstract

The functions of nucleic acids may be influenced by both their structural and dynamic properties. In this dissertation, two nucleic acid structural motifs were investigated. RNA pseudoknots were studied using NMR techniques, to gain improved understanding of their internal motions. The ligand interaction properties of DNA G-quadruplexes were studied using NMR and biochemical techniques. Some RNA pseudoknots are known to have an ability to stimulate frameshifting as the messenger RNA is translated by the ribosome. The dynamic properties of two representative frameshifting pseudoknots were investigated by vii evaluating 15N relaxation rates and proton exchange rates. The two pseudoknots were found to be similar in that the motions of all the observable 15N nuclei were tightly coupled with the overall molecular motion. However, the two pseudoknots differed in the exchange rates of the protons located in the vicinity of the junction of the helical stems. These results indicate that the flexibility between the two stems is not a required feature for a functional frameshifting pseudoknot. The G-quadruplex DNA is a secondary structure that can be formed at various locations in the human genome, most notably at the telomeric regions and the promoter regions. In this dissertation, a novel compound from the class of Fluoroquinophenoxazines called QQ58 was demonstrated to interact and stabilize G-quadruplex DNA from the telomeric region in vitro. This can lead to telomerase inhibition and disruption of protein-nucleic acid complexes at the telomeric ends. PIPER, a DNA G-quadruplex interactive compound, was shown to convert Watson-Crick base-paired duplex DNA to G-quadruplex DNA in a sequence selective manner. Studies in this dissertation have demonstrated that duplexes from the promoter region of c-myc oncogene and from the ciliate telomeric DNA were converted to G-quadruplex DNA in the presence of PIPER. However, there was no effect of PIPER on human telomeric duplex. The compounds studied in this dissertation have the potential to be applied in diagnostics as well as in anti-cancer therapeutics

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