Multiple Roles for Mono- and Poly(ADP-Ribose) in Regulating Stress Responses

Although stress-induced synthesis of mono(ADP-ribose) (mADPr) and poly(ADP-ribose) (pADPr) conjugates by pADPr polymerase (PARP) enzymes has been studied extensively, the removal and degradation of pADPr, as well as the fate of ADPr metabolites, have received less attention. The observations that stress-induced pADPr undergoes rapid turnover, and that deficiencies in ADPr degradation phenocopy loss of pADPr synthesis, suggest that ADPr degradation is fundamentally important to the cellular stress response. Recent work has identified several distinct families of pADPr hydrolases that can degrade pADPr to release pADPr or mADPr into the cytoplasm. Further, many stress-response proteins contain ADPr-binding domains that can interact with these metabolites. We discuss how pADPr metabolites generated during pADPr degradation can function as signaling intermediates in processes such as inflammation, apoptosis, and DNA damage responses. These studies highlight that the full cycle of ADPr metabolism, including both synthesis and degradation, is necessary for responses to genotoxic stress. DNA damage promotes the rapid production of pADPr chains on damaged chromatin and is crucial for initiating recruitment of DNA repair proteins. pADPr then undergoes rapid (seconds to minutes) degradation by PARG and related enzymes, releasing mADPr and soluble pADPr molecules into the nucleoplasm and cytoplasm. Many stress-response proteins contain ADP-ribose-binding modules with specificity for mADPr or pADPr, such that binding of specific pADPr metabolites can regulate DNA repair proteins and apoptosis during stress. A family of hydrolases which degrade mADPr, including NUDT5, can remove mADPr and terminate stress responses while generating useful metabolites. pADPr and its metabolites may function as novel stress-induced signaling molecules that regulate the function of stress and DNA repair proteins.