Protein poly(ADP-ribosyl)ation in genome stability and human disease. (360G-Wellcome-101794_Z_13_Z)

Poly(ADP-ribosyl)ation is a post-translational protein modification, synthesised by the PARP family of enzymes, that consists of long chains of repeating ADP-ribose nucleotide units. Through the modification of a variety of mediator proteins, PARPs control a number of cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the molecular players involved in these pathways and their mechanism s of regulation remain poorly understood. In recent years, blocking the PARP-regulated pathways using small-molecule inhibitors has become a promising strategy for treatment of cancer and acute cardiovascular conditions. For example, cell-permeable inhibitors targeting the PARP enzymes involved in DNA break repair demonstrated efficacy against certain types of cancer, such as hereditary breast or ovarian cancers. The intriguing alternative approaches to the chemical inhibition of PARPs include t argeting downstream protein effectors of PARP signalling and targeting PARG, the major enzyme that removes poly(ADP-ribosyl)ation. In the proposed studies, we will utilise a combination of biochemistry, cell biology and structural studies to improve our understanding of the function and regulation of PARG enzyme, and also to attempt developing the first specific cell-permeable human PARG inhibitors. Another goal of our studies is to screen for novel PARP-regulated DNA repair factors. Some of the identified proteins will be further characterised to elucidate their exact biochemical functions and regulation in DNA repair. Furthermore, we will explore the potential of these proteins to be exploited as targets for small molecule inhibitor design and cancer therapy.