Research project: DNA quadruplexes and their interaction with ligands

G-rich DNA sequences can fold into four-stranded structures which are based on stacks of G-quartets. Sequences with the potential to adopt this structure are common throughout the human genome, especially in gene promoters and within telomeric repeats. It is thought that some of these may play a role in controlling the activity of adjacent genes. We are studying the stability of different inter- and intramolecular DNA quadruplexes and their stabilization by small molecules.

It is well-known that DNA has a double helical structure, formed by the pairing of A with T and G with C. Although most cellular DNA is in this familiar form some DNA sequences can adopt alternative structures which contain three or four strands. In particular, sequences that are rich in Gs can fold to form a four-stranded structure which is based around stacks of G-quartets. These structures can be formed by folding a single DNA strand back on itself, generating stacks of G-quartets which are linked by loops between the four strands. Sequences with the potential to adopt this structure are common throughout the human genome, and it is thought that some of these may play a role in controlling the activity of adjacent genes. We are studying the stability of these structures in both linear fragments and in supercoiled DNA as well as their stabilisation by various quadruplex-binding ligands. We are also examining their effects on the expression of reporter genes. These studies will lead to a better understanding of the biological role of G-rich sequences and how they affect the activity of adjacent genes. These studies will facilitate the design of agents that can interfere with these processes and thereby enhance or inhibit gene activity.