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Title: Biophysical studies of the G-quadruplex motif
Author: Cousins, Alex R. O.
ISNI:       0000 0004 5362 4511
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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The occurrence of multiple adjacent G-quadruplex-forming motifs in the human genome, notably in the telomere, has promoted interest in how one adjacently positioned quadruplex affects another. A range of oligonucleotides were designed to feature one, two or three quadruplex-forming sequences and their biophysical properties were compared. CD, DSC, thermal denaturation experiments and supporting molecular simulations were the main techniques used. Sequences were based on the human telomeric sequence dAGGG(TTAGGG)3 and a parallel quadruplex-forming sequence dTGGGTGGGTTTGGGTGGG. Single and multiple telomeric quadruplexes formed similar topologies in equivalent quantities. Decreased thermal stability was observed for tandem quadruplexes. Divergence from a generally adequate two-state melting process was attributed to interaction between quadruplex subunits and domain-asymmetry. DSC analysis suggested that changes in heat capacity on folding were non-trivial and that quadruplex stabilities based on Van't Hoff enthalpy may be overestimated. Melting behaviour showed that topology of adjacent quadruplexes affects their interaction. Inter-quadruplex linker-length significantly affected topology and could induce domain asymmetry with 5' and 3' quadruplexes differing significantly in T m' Mixed telomeric and parallel quadruplex-forming sequences suggested that 5' quadruplexes were significantly destabilised by a 3' partner. Steric hindrance was a possible explanation. Quadruplex-binding ligands in the context of tandem quadruplexes were also investigated. Acridine derivative, RHPS4, increased thermal stability and induced topological changes in longer telomeric repeat sequences. A changed pattern of thermal stabilities hinted at an indirect effect on mutual quadruplex interactions via topological selection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available