ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1'' position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:21498885, PubMed:30830864, PubMed:33769608, PubMed:30045870, PubMed:29907568, PubMed:34321462, PubMed:30401461, PubMed:33186521, PubMed:34019811, PubMed:33894202, PubMed:34479984). Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:28650317, PubMed:29234005, PubMed:33186521, PubMed:30045870, PubMed:34019811). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802, PubMed:33186521). Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds (PubMed:16278211, PubMed:33769608). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:16278211). Also hydrolyzes free poly(ADP-ribose) in mitochondria (PubMed:22433848). Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (PubMed:17075046, PubMed:21498885). Specifically degrades 1''-O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers (PubMed:21498885). [(1''->2')-ADP-alpha-D-ribose](n) + H2O = [(1''->2')-ADP-alpha-D-ribose](n-1) + ADP-D-ribose 1''-O-acetyl-ADP-alpha-D-ribose + H2O = acetate + ADP-D-ribose + H(+) H2O + O-(ADP-D-ribosyl)-L-seryl-[protein] = ADP-D-ribose + L-seryl-[protein] alpha-NAD(+) + H2O = ADP-D-ribose + H(+) + nicotinamide Binds 2 magnesium ions per subunit. The protein undergoes a dramatic conformational switch from closed to open states upon substrate-binding, which enables specific substrate recognition for the 1''-O-linkage (PubMed:29907568, PubMed:34321462). The glutamate flap (Glu-41) blocks substrate entrance to Mg(2+) in the unliganded closed state (PubMed:30045870, PubMed:29907568, PubMed:34321462). In presence of substrate, Glu-41 is ejected from the active site: this closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1''-O-linkage for cleavage while securing tightly 2'- and 3'-hydroxyls of ADP-ribose (PubMed:30045870, PubMed:29907568, PubMed:34321462). Monomer. Recruited to DNA lesion regions following DNA damage; ADP-D-ribose-recognition is required for recruitment to DNA damage sites. Ubiquitous (PubMed:16278211). Expressed in skin fibroblasts (PubMed:30830864). The disease is caused by variants affecting the gene represented in this entry. Belongs to the ADP-ribosylglycohydrolase family.