ID   ADPRS_DANRE             Reviewed;         370 AA.
AC   Q66HT8; A7MCF6;
DT   06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT   02-SEP-2008, sequence version 2.
DT   02-SEP-2026, entry version 121.
DE   RecName: Full=ADP-ribosylhydrolase ARH3 {ECO:0000305};
DE   AltName: Full=ADP-ribose glycohydrolase ARH3 {ECO:0000305};
DE   AltName: Full=ADP-ribosylhydrolase 3 {ECO:0000250|UniProtKB:Q9NX46};
DE   AltName: Full=O-acetyl-ADP-ribose deacetylase ARH3 {ECO:0000305};
DE            EC=3.5.1.- {ECO:0000250|UniProtKB:Q9NX46};
DE   AltName: Full=Poly(ADP-ribose) glycohydrolase ARH3 {ECO:0000305};
DE            EC=3.2.1.143 {ECO:0000250|UniProtKB:Q9NX46};
DE   AltName: Full=[Protein ADP-ribosylarginine] hydrolase-like protein 2 {ECO:0000305};
DE   AltName: Full=[Protein ADP-ribosylserine] hydrolase;
DE            EC=3.2.2.-;
GN   Name=adprs;
GN   Synonyms=adprhl2 {ECO:0000250|UniProtKB:Q9NX46}, arh3
GN   {ECO:0000250|UniProtKB:Q9NX46};
GN   ORFNames=zgc:92867 {ECO:0000303|Ref.1};
OS   Danio rerio (Zebrafish) (Brachydanio rerio).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC   Danionidae; Danioninae; Danio.
OX   NCBI_TaxID=7955;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, and Ovary;
RG   NIH - Zebrafish Gene Collection (ZGC) project;
RL   Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: ADP-ribosylhydrolase that preferentially hydrolyzes the
CC       scissile alpha-O-linkage attached to the anomeric C1'' position of ADP-
CC       ribose and acts on different substrates, such as proteins ADP-
CC       ribosylated on serine and threonine, free poly(ADP-ribose) and O-
CC       acetyl-ADP-D-ribose. Specifically acts as a serine mono-ADP-
CC       ribosylhydrolase by mediating the removal of mono-ADP-ribose attached
CC       to serine residues on proteins, thereby playing a key role in DNA
CC       damage response. Serine ADP-ribosylation of proteins constitutes the
CC       primary form of ADP-ribosylation of proteins in response to DNA damage.
CC       Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or
CC       -asparagine bonds. Also able to degrade protein free poly(ADP-ribose),
CC       which is synthesized in response to DNA damage: free poly(ADP-ribose)
CC       acts as a potent cell death signal and its degradation by ADPRHL2
CC       protects cells from poly(ADP-ribose)-dependent cell death, a process
CC       named parthanatos (By similarity). Also hydrolyzes free poly(ADP-
CC       ribose) in mitochondria. Specifically digests O-acetyl-ADP-D-ribose, a
CC       product of deacetylation reactions catalyzed by sirtuins. Specifically
CC       degrades 1''-O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-
CC       ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers.
CC       {ECO:0000250|UniProtKB:Q9NX46}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[(1''->2')-ADP-alpha-D-ribose](n) + H2O = [(1''->2')-ADP-
CC         alpha-D-ribose](n-1) + ADP-D-ribose; Xref=Rhea:RHEA:52216, Rhea:RHEA-
CC         COMP:16922, Rhea:RHEA-COMP:16923, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:57967, ChEBI:CHEBI:142512; EC=3.2.1.143;
CC         Evidence={ECO:0000250|UniProtKB:Q9NX46};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=1''-O-acetyl-ADP-alpha-D-ribose + H2O = ADP-D-ribose + acetate
CC         + H(+); Xref=Rhea:RHEA:58112, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:30089, ChEBI:CHEBI:57967, ChEBI:CHEBI:142511;
CC         Evidence={ECO:0000250|UniProtKB:Q9NX46};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=O-(ADP-D-ribosyl)-L-seryl-[protein] + H2O = ADP-D-ribose + L-
CC         seryl-[protein]; Xref=Rhea:RHEA:58256, Rhea:RHEA-COMP:9863,
CC         Rhea:RHEA-COMP:15091, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999,
CC         ChEBI:CHEBI:57967, ChEBI:CHEBI:142556;
CC         Evidence={ECO:0000250|UniProtKB:Q9NX46};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=alpha-NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+);
CC         Xref=Rhea:RHEA:68792, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:17154, ChEBI:CHEBI:57967, ChEBI:CHEBI:77017;
CC         Evidence={ECO:0000250|UniProtKB:Q9NX46};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:Q9NX46};
CC       Note=Binds 2 magnesium ions per subunit.
CC       {ECO:0000250|UniProtKB:Q9NX46};
CC   -!- ACTIVITY REGULATION: The protein undergoes a dramatic conformational
CC       switch from closed to open states upon substrate-binding, which enables
CC       specific substrate recognition for the 1''-O-linkage. The glutamate
CC       flap (Glu-35) blocks substrate entrance to Mg(2+) in the unliganded
CC       closed state. In presence of substrate, Glu-35 is ejected from the
CC       active site: this closed-to-open transition significantly widens the
CC       substrate-binding channel and precisely positions the scissile 1''-O-
CC       linkage for cleavage while securing tightly 2'- and 3'-hydroxyls of
CC       ADP-ribose. {ECO:0000250|UniProtKB:Q9NX46}.
CC   -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:Q9NX46}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9NX46}. Cytoplasm
CC       {ECO:0000250|UniProtKB:Q9NX46}. Chromosome
CC       {ECO:0000250|UniProtKB:Q9NX46}. Mitochondrion matrix
CC       {ECO:0000250|UniProtKB:Q9NX46}. Note=Recruited to DNA lesion regions
CC       following DNA damage; ADP-D-ribose-recognition is required for
CC       recruitment to DNA damage sites. {ECO:0000250|UniProtKB:Q9NX46}.
CC   -!- SIMILARITY: Belongs to the ADP-ribosylglycohydrolase family.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH81683.1; Type=Miscellaneous discrepancy; Note=Unlikely isoform. Aberrant splice sites.; Evidence={ECO:0000305};
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DR   EMBL; BC081683; AAH81683.1; ALT_SEQ; mRNA.
DR   EMBL; BC152161; AAI52162.1; -; mRNA.
DR   RefSeq; NP_001004565.2; NM_001004565.2.
DR   AlphaFoldDB; Q66HT8; -.
DR   SMR; Q66HT8; -.
DR   FunCoup; Q66HT8; 628.
DR   STRING; 7955.ENSDARP00000027022; -.
DR   GlyGen; Q66HT8; 1 site, 1 O-linked glycan (1 site).
DR   PaxDb; 7955-ENSDARP00000027022; -.
DR   PeptideAtlas; Q66HT8; -.
DR   Ensembl; ENSDART00000011706; ENSDARP00000027022; ENSDARG00000019338.
DR   Ensembl; ENSDART00000181081; ENSDARP00000157106; ENSDARG00000110712.
DR   GeneID; 796446; -.
DR   KEGG; dre:796446; -.
DR   AGR; ZFIN:ZDB-GENE-040912-85; -.
DR   CTD; 54936; -.
DR   ZFIN; ZDB-GENE-040912-85; adprs.
DR   eggNOG; ENOG502QUER; Eukaryota.
DR   GeneTree; ENSGT00390000015369; -.
DR   HOGENOM; CLU_024566_6_0_1; -.
DR   InParanoid; Q66HT8; -.
DR   OMA; HMEHVEA; -.
DR   OrthoDB; 410104at2759; -.
DR   PhylomeDB; Q66HT8; -.
DR   Reactome; R-DRE-110362; POLB-Dependent Long Patch Base Excision Repair.
DR   PRO; PR:Q66HT8; -.
DR   Proteomes; UP000000437; Chromosome 17.
DR   Bgee; ENSDARG00000019338; Expressed in testis and 23 other cell types or tissues.
DR   GO; GO:0005694; C:chromosome; ISS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0090734; C:site of DNA damage; ISS:UniProtKB.
DR   GO; GO:0140292; F:ADP-ribosylserine-[protein] hydrolase activity; ISS:UniProtKB.
DR   GO; GO:0004553; F:hydrolase activity, hydrolyzing O-glycosyl compounds; ISS:UniProtKB.
DR   GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR   GO; GO:0061463; F:O-acetyl-ADP-ribose deacetylase activity; ISS:UniProtKB.
DR   GO; GO:0004649; F:poly(ADP-ribose) glycohydrolase activity; ISS:UniProtKB.
DR   GO; GO:0071451; P:cellular response to superoxide; IBA:GO_Central.
DR   GO; GO:0006281; P:DNA repair; ISS:UniProtKB.
DR   GO; GO:0060546; P:negative regulation of necroptotic process; ISS:UniProtKB.
DR   GO; GO:0140290; P:peptidyl-serine ADP-deribosylation; ISS:UniProtKB.
DR   FunFam; 1.10.4080.10:FF:000001; ADP-ribose glycohydrolase ARH3; 1.
DR   Gene3D; 1.10.4080.10; ADP-ribosylation/Crystallin J1; 1.
DR   InterPro; IPR050792; ADP-ribosylglycohydrolase.
DR   InterPro; IPR005502; Ribosyl_crysJ1.
DR   InterPro; IPR036705; Ribosyl_crysJ1_sf.
DR   PANTHER; PTHR16222; ADP-RIBOSYLGLYCOHYDROLASE; 1.
DR   PANTHER; PTHR16222:SF24; ADP-RIBOSYLHYDROLASE ARH3; 1.
DR   Pfam; PF03747; ADP_ribosyl_GH; 1.
DR   SUPFAM; SSF101478; ADP-ribosylglycohydrolase; 1.
PE   2: Evidence at transcript level;
KW   Chromosome; Cytoplasm; DNA damage; DNA repair; Hydrolase; Magnesium;
KW   Metal-binding; Mitochondrion; Nucleus; Reference proteome.
FT   CHAIN           1..370
FT                   /note="ADP-ribosylhydrolase ARH3"
FT                   /id="PRO_0000277616"
FT   BINDING         35
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         66
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         66
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         67
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         135..141
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         171
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         225
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         261
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         304
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         306
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         306
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   BINDING         307
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   SITE            35
FT                   /note="Glutamate flap"
FT                   /evidence="ECO:0000250|UniProtKB:Q9NX46"
FT   CONFLICT        345
FT                   /note="R -> H (in Ref. 1; AAI52162)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   370 AA;  40103 MW;  FC07F4F67AB7B784 CRC64;
     MSAAARVVAP VMMLSRFRGA LVGSVLGDCI GGEFEGAVDV PLDRVLQHLS ALEDDTRGDG
     ILQYSDDTAM MRCVADSLLT RMTFDERDMA QRFAKEYSHS PGRGYGSGVV QVLRKLASPH
     LKDVFQPAQA QFGGRGSFGN GGAMRAVPFA LAFRSRADVR KYSRFGAMLT HSCSLGYNGA
     ALQALAVHLS LQGALALPKD FIDKLISEME ELEKDETAKH DAKALNLSEF PYCSRLHRVK
     ELMDKTSVSI EEVISELGNG IAALQSVPTA IFCVLYCLEP QDGLPERFGG LERTIAYSLA
     LGGDTDTIAC MAGAIAGAHY GIDSIPLSWQ VSCEGVDEAD DLARRLYDLY CLPQHNEDRG
     NNQPHTTNTD
//