PARP-dependent DNA damage repair

The genome of organisms is under continual assault from a variety of agents that cause DNA damage. As such, cells have evolved a sophisticated set of pathways, collectively known as the DNA damage response (DDR), that detect, signal and repair DNA damage. These pathways are critical to maintain genome integrity and their dysfunction results in a variety of disease states including immunological deficiencies, neurodegeneration, premature ageing and cancer. Therefore, understanding the molecular basis of the DDR will provide insights into the molecular basis of an important biological process, in addition to knowledge to exploit in treating a range of pathologies, including cancer.
Poly-ADP-ribose polymerases (PARPs) are a critical component of the DDR that ADP-ribosylate protein substrates at sites of DNA damage to promote their repair. For example, PARP1 regulates DNA single strand break repair by modifying proteins at the DNA lesion and inhibition of this pathway using PARP inhibitors kills tumours with deficiencies in homologous recombination (HR). However, there are 17 different PARPs in humans, all of which are targets for currently available PARP inhibitors. An emerging theme is that many of these enzymes regulate different DNA repair processes. The molecular basis of how multiple PARPs function in distinct DNA repair mechanisms, whether there is cross-talk between these pathways, and how this impacts on the efficacy of PARP inhibitors to kill HR-defective cells is only poorly understood. The overall aims of this work are to address these important questions. This will include providing the student with a rigorous scientific training in a variety of molecular and cellular techniques that are applicable to the project, in addition to wider scientific skills including research project design, time and laboratory management, data analysis, presentation and written skills.
This work will not only provide insights into the molecular basis of how PARPs regulate DNA repair and genome stability, but also provide information to refine the use of PARP inhibitors in the clinic and guide the development of novel PARP inhibitors with new mechanisms of action.