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Title: Crystallographic and biophysical studies of telomeric RNA and DNA G-quadruplex-drug complexes
Author: Collie, William Gavin
ISNI:       0000 0004 2715 566X
Awarding Body: University of London
Current Institution: University of London
Date of Award: 2012
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The terminal regions of eukaryotic chromosomes - the telomeres - play a crucial role maintaining genomic integrity and in the regulation of cellular senescence and apoptosis. These regions - composed of a complex array of proteins and nucleic acid structures - are found to be dysregulated in a high percentage of cancers, and as a result, several components of mammalian telomeres are being actively investigated as potential anti- cancer drug targets. The work in this thesis has focused on a group of unusual nucleic acid structures which form from telomeric DNA and RNA molecules. These structures - termed G-quadruplexes - are of high relevance to anti-cancer drug design, as the stabilisation of such structures with small molecule compounds provides a therapeutic route to inhibiting a key oncogenic telomeric protein - telomerase. The overall aim of the work reported here has been to provide high resolution structural data - primarily in the form of X-ray crystal structures - concerning telomeric DNA and RNA G-quadruplexes, with a focus on the application of such structures to telomere- directed anti-cancer drug design. Several high resolution crystal structures of G- quadruplexes formed from human telomeric sequences were solved, providing atomic-scale details of RNA folding and G-quadruplex-drug interactions. The structures presented include the first crystallographic descriptions of native and ligand-bound G-quadruplexes formed from human telomeric RNA, as well as several human telomeric DNA G-quadruplex-ligand complexes, including the first complexes determined involving the much-studied human 22- mer sequence, d(AGGG[TIAGGGh). Additional biophysical data is also presented, complementing the crystallographic data by providing details of telomeric G-quadruplex higher-order structure formation, G-quadruplex stability and ligand-binding data. The high-resolution crystallographic structural data, combined with the biophysical findings, provide a comprehensive picture of telomeric G-quadruplex folding, ligand- recognition and multimerisation, and reveal important differences between telomeric DNA and RNA G-quadruplexes of relevance to the future design and development of telomeric G- quadruplex-directed therapeutic compounds.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available