My research interests lie in understanding how variations in DNA structure can affect fundamental biological processes such as replication and transcription. I am motivated by determining biomolecular mechanisms of action, with a long-term view to improved development of therapeutics. My current project aims to determine, at single molecule resolution, how topoisomerases relieve excessive torsional stress in DNA, and via which mechanism(s) their function is affected by topoisomerase inhibitors, a major class of antibiotic and anti-cancer therapeutics in collaboration with Prof Tony Maxwell (John Innes Centre).
Topoisomerases are enzymes, present in all organisms from humans to bacteria, which are essential for life due to their ability to untangle knotted and twisted DNA. The knotting and twisting of our DNA occurs as two metres of our DNA is folded into the cell nucleus; much narrower than the width of a human hair. This is exacerbated by the molecular machinery in our cells which travel along our DNA pulling it apart and manipulating it in a compact environment. Without topoisomerases, our DNA becomes irreversibly knotted and twisted and the cell will die. For this reason, key therapeutics such as anticancer and antibiotic drugs target human and bacterial topoisomerases respectively either killing cancerous or bacterial cells.
My research will provide insight into how topoisomerases are able to untwist DNA, and how this process can be disrupted by drugs. My research will exploit microscopy methods I pioneered to resolve the double helix on single DNA molecules in collaboration with Bruker (CA, USA). I will also perform rapid measurements of DNA-topoisomerase interactions at the Francis Crick Institute in collaboration with Dr Justin Molloy.