- DNA Interactions
- Triplex DNA
- Quadruplex DNA
- DNA Structure
My research concerns the sequence specific recognition of DNA by small molecules, oligonucleotides and proteins, and the formation of unusual DNA structures (triplexes and quadruplexes). Compounds that bind to DNA in a sequence specific fashion have potential for artificially controlling gene expression and may be used as anticancer or antiviral agents. Several DNA binding antibiotics are currently used in cancer chemotherapy, and we are seeking to understand the molecular mechanisms by which they bind to DNA with a view to designing new agents with improved selectivity. In all our studies we make extensive use of the footprinting technique, using both natural and synthetic DNA fragments, and have developed this assay as a powerful tool for measuring the specificity, stability and kinetics of ligand-DNA interactions. This has been used to determine the sequence selectivity of several DNA-binding small molecules.
For the past 20 years my work has focussed on triple helix formation as a means for targeting specific DNA sequences. Together with Professor Tom Brown (Oxford, Chemistry) I have developed several nucleotide analogues, which are designed to form stable triplexes under physiological conditions. Using a combination of these we demonstrated the first example of four base-pair recognition of a DNA sequence by a triplex-forming oligonucleotide at pH 7. In order to facilitate our studies on the stability of triplexes, quadruplexes and small-molecule-DNA complexes we developed a high throughput fluorescence assay for determining DNA melting profiles.
DNA quadruplexes can be formed by G-rich DNA sequences, and these may play a role in telomere structure or controlling gene expression. We have studied their biophysical properties studies, examining their stability, structure, and competition with DNA duplexes.