Protein ADP-ribosylation: DNA damage signalling and impacts on human health

Abstract

Genomic instability is the main driving force for cancer onset and progression, underlies the ageing process and is associated with neurodegenerative disease. Protein post-translational modification by NAD+-derived ADP-ribose moieties plays central roles in orchestrating the cellular DNA damage response, but most of the human enzymes that catalyze this modification, as well as the hydrolases that remove it, remain to be characterized. We have identified a role for the mono-ADP-ribosyl transferases PARP3, PARP9 and the ubiquitin ligase DTX3L in a common pathway that protects cells from a poorly defined form of DNA damage induced by the stabilization of G4 quadruplexes, a form of DNA secondary structure. Importantly, both PARP9 and DTX3L are recurrently overexpressed in diffuse large B-cell lymphomas (DLBCL) and mutations in histone H4 lysine 91, the target site for DTX3L ubiquitination, cause a human genetic disorder characterized by increased spontaneous DNA damage and neurodevelopmental defects. The first objective of this proposal is to characterize this novel DNA repair pathway in detail, with the aim of identifying disease mechanisms that may guide the future development of treatment options for these disorders. In a parallel project, we will study ARH3, another gene involved in a genetic neurological disorder, which encodes an ADP-ribosyl hydrolase whose cellular functions in response to DNA damage are currently unknown. In this proposal we combine research into fundamental biological mechanisms and human genetics, to shed light on the role of protein ADP-ribosylation in the DNA damage response and human disease. (AU)