Final Report Summary - MACDOPRO (Macro domain proteins in the cellular stress response and links to human disease)
Post-translational modification of proteins by ADP-ribosylation controls a number of essential cellular processes including DNA repair, regulation of chromatin structure, cell cycle checkpoint, transcription, apoptosis and mitosis. Many of these processes are known to be aberrant/deregulated in human disease; therefore increasing our understanding of how these processes work is of high importance. In addition, available data suggest that these processes in some instances could be actively targeted by inhibitors/modulators for the therapeutic benefit. One class of proteins that can sense ADP-ribosylation signalling and regulate ADP-ribosylation-dependent pathways are macro domain proteins. Our studies provided important mechanistic and structural insight into how these enzymes work and how the function of these proteins links to human disease. Specifically we have studied two human enzymes PARG (the main enzyme in cells that removes ADP-ribosylation marks from proteins) and ALC1 (a chromatin remodelling enzyme deregulation of which leads to development of cancer) and provided a deeper understanding of their mechanism of catalysis and their protein-protein interactions. In addition, we have biochemically characterised a special type of macro domain proteins found exclusively in fungal and bacterial pathogens and analyzed their importance to support the pathogenic mechanisms against humans as well as their role in the response to oxidative stress.