ADPribosylhydrolase

ADP-ribosylhydrolase refers to enzymes that reverse ADP-ribosylation by removing ADP-ribose units from target substrates, thereby counteracting a post-translational modification that regulates diverse cellular processes. In humans, several distinct ADP-ribosylhydrolases have been characterized, belonging mainly to two families with different substrate specificities: ARH (ADP-ribosylhydrolase) enzymes and macrodomain-containing hydrolases.

The ARH family includes ARH1 and ARH3. ARH1 hydrolyzes mono-ADP-ribosylation on arginine residues of proteins, effectively reversing Arg-ADP-ribosylation. ARH3 primarily targets serine-linked ADP-ribosylation; in cells, serine MARylation is promoted by HPF1, and ARH3 acts to remove these modifications, contributing to restoration of unmodified proteins after DNA damage signaling and stress responses.

Macrodomain-containing hydrolases comprise MacroD1, MacroD2, and TARG1 (also called OARD1). These enzymes efficiently remove mono-ADP-ribose from acidic residues, particularly aspartate and glutamate, on proteins and can act on free MAR units as well. The macrodomain hydrolases form a separate family from ARHs and have overlapping but distinct substrate preferences compared with ARH1 and ARH3.

Biological roles of ADP-ribosylhydrolases include regulation of DNA repair, transcriptional control, chromatin remodeling, and cellular stress responses. They help terminate MARylation signals, maintain protein function, and prevent excessive damage signaling. Dysregulation of these enzymes can affect genome stability and cellular homeostasis, making them of interest for studies of aging, neurobiology, and cancer biology.