What comes to mind when you think of DNA? Most people think of the iconic double helix structure, however DNA can adopt a wide variety of alternative secondary structures inside cells. The intercalated (i) motif is a quadruplex (four stranded) structure formed by cytosine-rich sequences upon protonation. i-Motifs are known to play an important role in gene regulation and have applications in nanotechnology.1
The folding of DNA into an i-motif depends upon many interconnected factors, including the pH, salt concentration, solvent composition, temperature, and the presence of DNA-binding drugs such as mitoxantrone. Understanding these factors is crucial to reveal the biological role of i-motifs and to develop new therapeutics and nanomachines. However, experimental investigation of i-motifs is very challenging due to the high number of variables involved.
In this 3.5-year PhD studentship funded by the Leverhulme Trust, you will develop a whole new approach to the analysis of i-motif DNA in which the conditions of a sample are varied continuously and reversibly using controlled concentration gradients. The gradients of pH, salt or DNA-binding molecules are analysed using localised nuclear magnetic resonance (NMR), allowing analysis of DNA under different conditions in single experiments.2,3 Having developed tools to mimic intracellular variations in pH, you will apply your skills to investigate the effect of other conditions on the critical pH at which i-motifs form, and how this information can be used to reveal the mechanism of action of DNA-binding drugs.
Based in the School of Pharmacy at UEA, you will join a diverse community of researchers with interests spanning pharmaceutical materials, pharmacology and medicinal chemistry. You will also work with the group of Dr Zoë Waller at University College London, where you will learn how to prepare samples of DNA for analysis and perform complementary analytical measurements including fluorescence assays and circular dichroism.
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