While stress-induced synthesis of mono ADP-ribose (mADPr) and poly ADP-ribose (pADPr) conjugates by PARP enzymes has been studied extensively, the removal and degradation of pADPr, and the fate of ADPr metabolites has received less attention. The observations that stressinduced pADPr undergoes rapid turnover and 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 hydrolyases 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. Here, we will 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. Conjugation of ADP-ribose (ADPr) to proteins plays a critical signaling function in gene transcription, chromatin organization and stress responses. Poly-ADPr polymerase (PARP1) was originally thought responsible for producing all cellular ADPr (1). However, PARP1 is one of 18 human enzymes (also known as diphtheria toxin-type ADP-ribose transferases (ARTDs, See Glossary), reviewed in (2)), which can ADP ribosylate proteins. Further, families of ADPr hydrolases which cleave pADPr chains, protein-ADPr bonds or which remove the terminal mADPr from pADPr chains have been identified. In addition, multiple ADPr binding domains have been described. There are therefore both writers and erasers of ADPr as well as protein modules that can read mADPr and pADPr. Protein-mADPr, pADPr polymers (both protein-linked and soluble) and free mADPr may therefore represent distinct functional signaling effectors in the cell.

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