Fig. 3
From: Emerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation
Reversal of protein ADP-ribosylation by MAR and PAR erasers. The diagrams represent MARylated (upper panel) and PARylated proteins (lower panel) with bond-specific chemical cleavage sites for each eraser. A subgroup of erasers that comprises MacroD1, MacroD2, and ARH1 are MAR-specific erasers involved in the removal of single ADP-ribose adducts. MacroD1 and MacroD2 are macrodomain-containing enzymes that release ADP-ribose from ADP-ribosylated acidic residues (aspartate and glutamate). ARH1 is currently the only known MAR hydrolase that specifically removes MAR from arginine residues. A second subgroup that includes TARG1, ARH3, NUDT9, NUDT16, and ENPP1 can target both MAR and PAR modifications. The TARG1 macroprotein hydrolyzes glutamate-ADP-ribose bonds and releases ADP-ribose from MARylated proteins. TARG1 has also the unique ability to remove entire PAR chains from acidic residues of PARylated proteins. ARH3 is limited to exoglycosidic activity toward PAR chains and releases free ADP-ribose. In addition, it possesses MAR hydrolase activity specifically targeting the O-linked ADP-ribosylation. NUDT9 and NUDT16 have nucleoside diphosphate-linked moiety-X (NUDIX) domains, which cleave pyrophosphate bonds and release phospho-ribosyl-AMP from PAR chains or AMP from MARylated proteins as major reaction products. ENPP1 is a pyrophosphatase lacking a NUDIX domain but with the capability of digesting PAR and MAR modifications similar to NUDIX enzymes. PARG is the main PAR-degrading enzyme but shows no activity towards MARylated proteins. Human PARG is unable to cleave the proximal ADP-ribose groups from a modified protein but possesses exo- and endoglycosidic activities to hydrolyze the glycosidic bonds between ribose units of PAR. The exoglycosidic activity of PARG generates free ADP-ribose from the processive degradation of PAR from the distal to the proximal end while its in-chain cleavage activity (endoglycosidic) produces protein-free PAR. The endoglycosidic degradation of PAR by of PARG is also responsible for the hydrolysis of the branching points formed when non-adenine riboses are linked together (branching point)
