Prof Nick Lakin

Detection, Signalling and Repair of DNA Damage

Preserving the integrity of genetic material is of critical importance to the health of an organism – if this goes wrong cells accumulate mutations in their genomes, resulting in a variety of diseases including cancer. Cells have therefore developed ways to detect DNA damage when it occurs and to signal this to the cell so that it can initiate its repair. We have a long-standing interest in these systems and exploiting this knowledge to treat a variety of diseases, including cancer.

Poly ADP-ribose polymerases - or PARPs – are a cornerstone of the cell’s response to DNA damage. They detect breaks in the DNA double strand helix and attach ADP-ribose onto proteins situated at the DNA damage site. This acts as a signal to bring in proteins that repair the damage. Our recent work discovered that several types of PARP respond to different varieties of DNA damage – this acts to recruit the most appropriate proteins to repair a particular type of DNA damage. Our current work aims to discover how this regulation works by: a) establishing how different PARPs modify different proteins at different DNA damage sites. b) Discover proteins that bind these modified proteins – reading the ADP-ribosylation code to promote recruitment of the appropriate DNA repair proteins. c) Assess how these pathways interact with each other to promote cell survival in response to damaged DNA. Our long-term vision is to understand how defects in DNA repair promote cancer and to exploit this knowledge in cancer therapies.