ADP-ribosylation signalling in genome stability

ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and the mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as the major form of DNA damage induced ADPr and decoded the mechanism for the synthesis (by PARP/HPF1 complexes) and removal (by cooperation between ARH3 and PARG hydrolases) of this modification. We also recently identified the Tyr-ADPr as a novel form of ADPr. One goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1, PARG and ARH3 work in the synthesis/removal of Ser- and Tyr-ADPr. Another goal is to define the physiological processes controlled by Ser- and Tyr-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.