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Fig. 1. Metabolism of poly(ADP-ribose). Poly(ADP-ribose) polymerase-1 (PARP-1) hydrolyzes NAD+ to polymerize ADP-ribose units on substrate proteins, with the concomitant release of nicotinamide. PARP-1 catalyzes the three steps of poly(ADP-ribose) anabolism (red part of the cycle): (1) mono(ADP-ribosyl)ation of the acceptor protein substrate; (2) elongation; and (3) branching of the poly(ADP-ribose) chain. Branching occurs on average every 20-50 ADP-ribose units (Alvarez-Gonzalez and Jacobson, 1987). The catalytic activities of other PARPs remain to be characterized. They catalyze mono and poly(ADP-ribosyl)ation reactions but may not all be able to carry out the branching reaction. The negatively charged poly(ADP-ribose) has a short half-life owing to poly(ADP-ribose) glycohydrolase (PARG) (green side of the cycle) that is activated by an increase in the cellular concentration of poly(ADP-ribose). PARG carries exoglycosidic and endoglycolytic activities that cleave glycosidic bonds between ADP-ribose subunits located at the ends and within the poly(ADP-ribose) chains, respectively (cleavage sites shown by dark green arrows). The release of the most proximal ADP-ribose unit from the acceptor protein (cleavage site shown by the light green arrow) can be catalyzed by PARG (Desnoyers et al., 1995) and/or by ADP-ribosyl protein lyase (Oka et al., 1984).

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