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Title: DNA quadruplex systems and their interactions with anti-cancer drugs: a small angle solution scattering study
Author: Miles, Shirley
Awarding Body: Keele University
Current Institution: Keele University
Date of Award: 2008
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DNA quadruplexes are involved in the regulation of gene expression, recombination and chromosomal alignment. They have been extensively studied using telomeric DNA sequences. Their overall conformation depends on the number of DNA strands (one, two or four) and on ionic conditions and it has been suggested that this behaviour may relate to regulatory mechanisms. Several proteins, including telomerase, have high binding affinities for quadruplexes. Telomerase function has been implicated with the immortality of cancer cells. Stabilising quadruplexes by small ligands has been used to inhibit telomerase function, thus providing a target for anti-cancer therapies. Chapters 3 and 4 describe detailed small angle scattering studies of K+ and Na' concentration effects on monomeric, dimeric and tetrameric quadruplexes in solution, both in the absence and presence of a small ligand. The results of Chapter 3 show that K+ and Na+ have markedly different effects on quadruplex structure in solution, further supporting the idea that the balance of these ionic species may be important in regulatory processes. The results of Chapter 4 extend these observations and show that the interaction of the acridine drug depends critically on the type of quadruplex involved - with clear evidence to suggest that the drug interaction is more favoured for quadruplex structures having extended loops. Chapter 5 describes solution scattering studies of the melting/annealing of monomeric and tetrameric quadruplexes as a function of temperature. Ab initio shape determination was used to study folding pathways, and models for the denatured, fully formed and intermediate quadruplex species are presented. These results show that the tetrameric quadruplex does not melt in the presence of K+, emphasising the clear structural differences in the two ionic environments and raise the intriguing possibility that this difference in behaviour for the two salts could be implicated in biological control/switching processes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available