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Information on EC 3.2.1.143 - poly(ADP-ribose) glycohydrolase and Organism(s) Mus musculus and UniProt Accession Q8CG72
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3.2.1.143 poly(ADP-ribose) glycohydrolaseSpecify your search results
Word Map
- 3.2.1.143
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polyadp-ribose
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polyadp-ribosylation
- parp-1
- polymerase-1
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adp-ribosylation
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genotoxic
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parylation
- gallotannins
- analysis
- drug development
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parthanatos
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automodification
-
adp-ribosylhydrolase
- pharmacology
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padpr
- olaparib
- molecular biology
- aif
- medicine
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
poly(adp-ribose) glycohydrolase, parg1, par glycohydrolase, poly (adp-ribose) glycohydrolase, adprhl2, poly(adp-ribose)glycohydrolase, parg110, adp-ribose glycohydrolase, drparg, adp-ribosyl-acceptor hydrolase 3, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ADP-ribose glycohydrolase
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Genbank AB019366-derived protein GI 6518480
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Genbank U78975-derived protein GI 2062407
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glycohydrolase, poly(adenosine diphosphoribose)
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glycohydrolase, poly(adenosine diphosphoribose) (cattle clone 4/5)
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glycohydrolase, poly(adenosine diphosphoribose) (Rattus norvegicus strain BUF gene Parg)
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PARG
poly(adenosine diphosphoribose) glycohydrolase
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poly(adenosine diphosphoribose) glycosidase
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poly(ADP-ribose) glycohydrolase (Arabidopsis thaliana gene At2g31860)
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poly(ADP-ribose) glycohydrolase (Arabidopsis thaliana gene At2g31870)
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poly(ADP-ribose) glycohydrolase (cattly clone 4/5)
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poly(ADP-ribosyl) glycohydrolase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hydrolyses poly(ADP-D-ribose) at glycosidic (1''-2') linkage of ribose-ribose bond to produce free ADP-D-ribose
catalytic mechanism, structure-function analysis, overview
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of O-glycosyl bonds
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CAS REGISTRY NUMBER
COMMENTARY
190209-88-2
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253766-41-5
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253766-42-6
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253767-74-7
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9068-16-0
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
poly(ADP-ribose)n + H2O
ADP-ribose
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and lower molecular weight poly(ADP-ribose)n fragment products, no product: phosphoribosyl-AMP
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?
histone-bound poly(ADP-ribose) + H2O
ADP-ribose + ADP-ribose oligomer + ?
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C14-labelled poly(ADP-ribose) produced by PARP-1 (poly(ADP-ribose) polymerase) of labelled NAD+
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?
poly(ADP-D-ribose)n + H2O
poly(ADP-D-ribose)n-1 + ADP-ribose
binding structure of ADP-ribose to wild-type and mutant enzymes, overview
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?
additional information
?
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no substrate: mono-ADP-ribosylated proteins, ADP-ribose-arginine, ADP-ribose-cysteine, ADP-ribose-diphthaminde, ADP-ribose-asparagine
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?
additional information
?
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enzyme is a necessary component of the poly(ADP-ribose) polymerase 1 mediated cell death pathway
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?
additional information
?
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enzyme activity modulates the inflammatory response and tissue events associated with spinal cord trauma and participates in target organ damage under these conditions
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
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enzyme is a necessary component of the poly(ADP-ribose) polymerase 1 mediated cell death pathway
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?
additional information
?
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enzyme activity modulates the inflammatory response and tissue events associated with spinal cord trauma and participates in target organ damage under these conditions
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?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
adenosine 5'-diphosphate-(hydroxymethyl)-pyrrolidinediol
ADP-HPD, an analogue of ADP-ribose
gallotannin
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inhibition of enzyme activity. In presence of inhibitor, reduction of cell death after exposure to hydrogen peroxide, N-methyl-D-aspartate, or N-methyl-N-nitro-N-nitrosoguanidine
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GPI 16552
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pharmacological inhibitor, treatment of wild-type mice shows a protective effect in dinitrobenzene sulfonic acid-induced colitis
GPI 18214
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pharmacological inhibitor, treatment of wild-type mice shows a protective effect in dinitrobenzene sulfonic acid-induced colitis
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N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide
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i.e. GPI 16552, pharmacological inhibitor. Enzyme inhibition results in significant reduction of spinal cord inflammation and tissue injury, neutrophil infiltration, cytokine production, and apoptosis upon spinal cord injury. Additionally, inhibition significantly ameliorates the recovery of limb function
nobotanin B
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inhibition of enzyme activity. In presence of inhibitor, reduction of cell death after exposure to hydrogen peroxide, N-methyl-D-aspartate, or N-methyl-N-nitro-N-nitrosoguanidine
phosphorodiamidate morpholino oligonucleotide
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antisense phosphorodiamidate morpholino oligonucleotide blocks exon 1 of the full length nuclear PARG 111 kDa isoform, slowing down the rate of nuclear poly(ADP-ribose) degradation, attenuating poly(ADP-ribose) polymerase-1 mediated cell death, reducing PARG expression as shown by immunostaining, upon incubation with 50 microM alcylating agent N-methyl-N'-nitro-N'-nitrosoguanidine to induce cell death blocking of nuclear PARG reduced cell condensation and cell death, no inhibitory influence on cytosol PARG
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additional information
the N-terminal regulatory fragment can activate in trans the inactive enzyme fragment depleted with this segment. This suggests that, whereas the enzyme activity can be inhibited by disrupting the docking of this segment to its enzyme binding groove (via posttranslational modification or protein-proteins interactions), the enzyme can be reversibly activated once the disruptive factor is removed
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additional information
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the N-terminal regulatory fragment can activate in trans the inactive enzyme fragment depleted with this segment. This suggests that, whereas the enzyme activity can be inhibited by disrupting the docking of this segment to its enzyme binding groove (via posttranslational modification or protein-proteins interactions), the enzyme can be reversibly activated once the disruptive factor is removed
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
the N-terminal regulatory fragment can activate in trans the inactive enzyme fragment depleted with this segment. This suggests that, whereas the enzyme activity can be inhibited by disrupting the docking of this segment to its enzyme binding groove (via posttranslational modification or protein-proteins interactions), the enzyme can be reversibly activated once the disruptive factor is removed
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additional information
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the N-terminal regulatory fragment can activate in trans the inactive enzyme fragment depleted with this segment. This suggests that, whereas the enzyme activity can be inhibited by disrupting the docking of this segment to its enzyme binding groove (via posttranslational modification or protein-proteins interactions), the enzyme can be reversibly activated once the disruptive factor is removed
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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primary culture, highest ratio of nuclear to cytoplasmic enzyme activity
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primary culture of astrocytes, neurons, and C6 glioma cells, no overall differences in enzyme activity between these cell types
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primary culture, lowest ratio of nuclear to cytoplasmic enzyme activity
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
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knockout mutants of isozyme PARG110 show resistance to photoreceptor degeneration, the mutant retina is morphologically and functionally undistinguishable from wild-type. Absence of PARG110 disrupts the poly-ADP-ribose polymerase activation
metabolism
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isozyme PARG110 and poly-ADP-ribose polymerase-1 act in a positive feedback loop, which is especially active under pathologic conditions
physiological function
additional information
physiological function
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poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death. Transient receptor potential 2 is the primary Ca2+ channel for cell death signaling under poly(ADP-ribose)glycohydrolase control
physiological function
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causal involvement of wild-type isozyme PARG110 in the process of photoreceptor degeneration. Contrasting its anticipated role as a functional antagonist, absence of PARG110 correlated with low PARP activity, suggesting that PARG110 and PARP1 act in a positive feedback loop, which is especially active under pathologic conditions
physiological function
protein poly(ADP-ribosyl)ation regulates a number of important cellular processes. Poly(ADP-ribose) glycohydrolase is the primary enzyme responsible for hydrolyzing the poly(ADP-ribose) polymer in vivo
additional information
E748 and E749 are the key catalytic residues in the signature loop, N733 directly recognizes the 3'-OH on the proximal ribose, catalytic domain structure in apo- and liganded-states, overview. The N-terminal flexible peptide preceding the enzyme's catalytic domain may regulate the enzymatic activity, catalytic and regulatory mechanisms, overview. A binding site outside of the catalytic cleft for iso-ADP-ribose, which is probably the smallest enzyme subtrate containing the alpha(1->2) ribose-ribose glycosidic bond, may explain the processivity of the enzyme activity
additional information
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E748 and E749 are the key catalytic residues in the signature loop, N733 directly recognizes the 3'-OH on the proximal ribose, catalytic domain structure in apo- and liganded-states, overview. The N-terminal flexible peptide preceding the enzyme's catalytic domain may regulate the enzymatic activity, catalytic and regulatory mechanisms, overview. A binding site outside of the catalytic cleft for iso-ADP-ribose, which is probably the smallest enzyme subtrate containing the alpha(1->2) ribose-ribose glycosidic bond, may explain the processivity of the enzyme activity
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ADPRS_MOUSE
370
0
39414
Swiss-Prot
Mitochondrion (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme catalytic domain free or in complexes with ADP-ribose and inhibitor ADP-HPD, as well as four enzyme catalytic residues mutants, X-ray diffraction structure determination and analysis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D77N/D78N
no enzymic activity, binding of ADP-ribose is similar to wild-type
E748N
site-directed mutagenesis, the mutant is inactive, activity is disrupted due to significant conformational changes
E748Q
site-directed mutagenesis, the mutant activity is highly reduced compared to the wild-type enzyme
E749N
site-directed mutagenesis, the mutant is inactive, activity is disrupted due to significant conformational changes
E749Q
site-directed mutagenesis, the mutant activity is highly reduced compared to the wild-type enzyme
F868A
site-directed mutagenesis, the mutant activity is reduced compared to the wild-type enzyme
G737A/G738A
site-directed mutagenesis, the mutant activity is reduced compared to the wild-type enzyme
G866A
site-directed mutagenesis, the mutant activity is reduced compared to the wild-type enzyme
additional information
additional information
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deletion of enzyme gene by gene targeting in embryonic stem cells and mice, severe compromisation of automodification of poly(ADP-ribose) polymerase 1. Enzyme deficient mice are viable and fertile, but hypersensitive to alkylating agents and ionizing radiation, and susceptible to streptozotocin-induced diabetes and endotoxic shock
additional information
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enzyme knockout mutation is lethal. Silencing by RNA interference results in 10% of enzyme protein that are sufficient to ensure normal proliferation through several subculturing rounds and cells that are able to repair DNA damage induced by sublethal doses of H2O2. Silenced cells are more resistant than wild-type to oxidant-induced apoptosis while exhibiting delayed poly(ADP-ribose) degradation and transient accumulation of ADP-ribose polymers
additional information
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disruption of poly(ADP-ribose) glycohydrolase gene results in significant reduction of spinal cord inflammation and tissue injury, neutrophil infiltration, cytokine production, and apoptosis upon spinal cord injury
additional information
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hypomorphic mouse model in which exons 2 and 3 of PARG gene have been deleted. Mutants exhibits nuclear localization of the enzyme which contains a catalytic domain but lacks the N-terminal region. Following DNA damage induced by N-methyl-N'-nitro-N-nitrosoguanidine, activity of both poly(ADP-ribose) glycohydrolase and poly(ADP-ribose) polymerase in mutant cell increases. Increase in poly(ADP-ribose) glycohydrolase activity leads to decrease in poly(ADP-ribose) polymerase-1 automodification resulting in increased activity. Mutant cells also show reduced formation of XCRR1 foci, delayed H2AX phosphorylation, decreased DNA break intermediates during repair, and increased cell death
additional information
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mice lacking the functional 110 kDa isoform of enzyme are resistant to colon injury by dinitrobenzene sulfonic acid. Mucosa of mutant mice colon tissue shows reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Overproduction of proinflammatory factors tumor necrosis factor alpha and interleukin 1beta and activation of cell death signaling pathway are inhibited in these mice
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
the enzyme is a target for development of specific inhibitors
medicine
medicine
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enzyme activity modulates the inflammatory response and tissue events associated with spinal cord trauma and participates in target organ damage under these conditions
medicine
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treatment of wild-type mice with pharmacological inhibitors GPI 16552 or GPI 18214 shows a protective effect in dinitrobenzene sulfonic acid-induced colitis. Mice lacking the functional 110 kDa isoform of enzyme are resistant to colon injury by dinitrobenzene sulfonic acid. Mucosa of mutant mice colon tissue shows reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Overproduction of proinflammatory factors tumor necrosis factor alpha and interleukin 1beta and activation of cell death signaling pathway are inhibited in these mice
medicine
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the enzyme is a potential target for neuroprotective treatments for retinal degeneration
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Blenn, C.; Althaus, F.R.; Malanga, M.
Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death
Biochem. J.
396
419-429
2006
Mus musculus
Sevigny, M.B.; Silva, J.M.; Lan, W.C.; Alano, C.C.; Swanson, R.A.
Expression and activity of poly(ADP-ribose) glycohydrolase in cultured astrocytes, neurons, and C6 glioma cells
Brain Res. Mol. Brain Res.
117
213-220
2003
Mus musculus
Oka, S.; Kato, J.; Moss, J.
Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase
J. Biol. Chem.
281
705-713
2006
Mus musculus (Q8CG72), Homo sapiens (Q9NX46), Homo sapiens
Cortes, U.; Tong, W.M.; Coyle, D.L.; Meyer-Ficca, M.L.; Meyer, R.G.; Petrilli, V.; Herceg, Z.; Jacobson, E.L.; Jacobson, M.K.; Wang, Z.Q.
Depletion of the 110-kilodalton isoform of poly(ADP-ribose) glycohydrolase increases sensitivity to genotoxic and endotoxic stress in mice
Mol. Cell. Biol.
24
7163-7178
2004
Mus musculus
Ying, W.; Sevigny, M.B.; Chen, Y.; Swanson, R.A.
Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death
Proc. Natl. Acad. Sci. USA
98
12227-12232
2001
Mus musculus
Gao, H.; Coyle, D.L.; Meyer-Ficca, M.L.; Meyer, R.G.; Jacobson, E.L.; Wang, Z.Q.; Jacobson, M.K.
Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase
Exp. Cell Res.
313
984-996
2007
Mus musculus
Cuzzocrea, S.; Mazzon, E.; Genovese, T.; Crisafulli, C.; Min, W.K.; Di Paola, R.; Muia, C.; Li, J.H.; Malleo, G.; Xu, W.; Massuda, E.; Esposito, E.; Zhang, J.; Wang, Z.Q.
Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice
Free Radic. Biol. Med.
42
90-105
2007
Mus musculus
Cuzzocrea, S.; Genovese, T.; Mazzon, E.; Crisafulli, C.; Min, W.; Di Paola, R.; Muia, C.; Li, J.H.; Esposito, E.; Bramanti, P.; Xu, W.; Massuda, E.; Zhang, J.; Wang, Z.Q.
Poly(ADP-ribose) glycohydrolase activity mediates post-traumatic inflammatory reaction after experimental spinal cord trauma
J. Pharmacol. Exp. Ther.
319
127-138
2006
Mus musculus
Burns, D.M.; Ying, W.; Kauppinen, T.M.; Zhu, K.; Swanson, R.A.
Selective down-regulation of nuclear poly(ADP-ribose) glycohydrolase
PLoS ONE
4
e4896
2009
Mus musculus
Blenn, C.; Wyrsch, P.; Bader, J.; Bollhalder, M.; Althaus, F.R.
Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death
Cell. Mol. Life Sci.
68
1455-1466
2011
Mus musculus
Sahaboglu, A.; Tanimoto, N.; Bolz, S.; Garrido, M.G.; Ueffing, M.; Seeliger, M.W.; Loewenheim, H.; Ekstroem, P.; Paquet-Durand, F.
Knockout of PARG110 confers resistance to cGMP-induced toxicity in mammalian photoreceptors
Cell Death Dis.
5
e1234
2014
Mus musculus
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