Use this URL to cite or link to this record in EThOS:
Title: Crystallographic and biophysical studies of telomeric RNA and DNA G-quadruplex-drug complexes
Author: Collie, Gavin William
ISNI:       0000 0004 2715 566X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2012
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
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[TTAGGG]3). 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