New players to the field of ADP-ribosylation make the final cut.

ADP-ribose-based intermediates, including PARP-generated monoand poly(ADP-ribose) post-translational modifications, are important to a number of cellular signalling processes. The reversal of poly(ADP-ribosyl)ation is mostly attributed to PARG, which however cannot remove the final protein-linked mono(ADP-ribose) residue. Three recent studies, one of them in The EMBO Journal, now report that certain macrodomains remove terminal ADPribose modifications from acidic residues. ADP-ribosylation is a post-translational modification (PTM) in which the ADP-ribose moiety of NAD is covalently transferred to a target protein (see Figure 1). This reaction is catalysed by poly(ADP-ribose) polymerase (PARP) enzymes, some of which also extend the modification by adding additional ADP-ribose molecules through riboseribose bonds, thus generating poly(ADP-ribose) (PAR). PARP1 and PARP2 account for the majority of PAR formation in response to cellular stress such as DNA damage. Poly(ADP-ribosyl)ation is a dynamic and transient modification event, since an enzyme called poly(ADP-ribose) glycohydrolase (PARG) counters PARP activities by degrading PAR through endoand exo-glycosidic activities (see Figure 1). However, neither PARG nor the unrelated ADPribosyl hydrolase 3 (ARH-3) also implicated in PAR hydro-