Mechanism and inhibition of the DNA repair enzyme Tdp1

Supervisors: Dr Julia Richardson, Dr Heidrun Interthal

Project Description:

DNA topoisomerases are described as “magicians of the DNA world”. They allow DNA strands and double helices to “pass through each other” thereby resolving topological strain created during DNA replication and transcription. To work their magic, topoisomerases form a covalent complex with DNA. But, if this complex is stalled, DNA damage ensues, leading to potentially lethal DNA double strand breaks. This is the mode-of-action of topoisomerase inhibitors.   

Fortunately, the cell has a back-up plan: it can process stalled Topo IB-DNA complexes using the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1).  Tdp1 hydrolyses the phosphodiester bond between a tyrosine side-chain on Topo IB and a DNA 3’ phosphate allowing the damaged DNA ends to be repaired.
Blocking DNA repair by targeting human Tdp1 with small molecule inhibitors could be a useful adjunct to topoisomerase-based therapeutics.

Our objectives are:
(1)    To understand at the molecular level how human Tdp1 recognises, binds and processes its physiological Topo IB-DNA substrate.
(2)    To identify how Tdp1 inhibitors bind to Tdp1 and block its activity.

We will use complementary structural and biochemical approaches, along with in vitro and in vivo assays developed in the Interthal lab.

The student will develop a broad range of skills in structural biology and biochemistry (in the Richardson lab) and in the molecular biology of DNA repair (in the Interthal lab).

If you wish to apply for this project, please go to this link.