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Gene Review

PARG  -  poly (ADP-ribose) glycohydrolase

Homo sapiens

Synonyms: Poly(ADP-ribose) glycohydrolase
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Disease relevance of PARG

  • Further analysis of PARP-1, PARG and other PARP family genes should extend our understanding of the pathogenesis of cancer and autoimmune diseases [1].
  • Role of poly(ADP-ribose) glycohydrolase (PARG) in shock, ischemia and reperfusion [2].
  • Accordingly, modulation of PAR synthesis or degradation through the targeting of PARP-1 or PARG holds particular promise in the treatment of conditions such as cancer, stroke, and Parkinson's disease [3].
  • This study evaluates enterogastric reflux (EGR) levels in patients with and without symptoms of postoperative alkaline reflux gastritis (PARG) after gastric surgery [4].
  • Small molecule inhibitors of PARP and PARG have shown considerable promise in cellular models of ischemia-reperfusion injury and oxidative neuronal cell death [5].

High impact information on PARG

  • The NAD+-dependent activities of PARP-1 are reversed by PARG, a poly(ADP-ribose) glycohydrolase, and are inhibited by ATP [6].
  • PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death [7].
  • Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls [7].
  • Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures [7].
  • The hydrolysis of poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase (PARG) was also required, since specific PARG inhibitors, which limit the production of ADP-ribose molecules, restored the function of ABC transporters [8].

Biological context of PARG

  • PARG [poly(ADP-ribose) glycohydrolase] is the only known enzyme that catalyses the hydrolysis of poly(ADP-ribose), a branched polymer that is synthesized by the poly(ADP-ribose) polymerase family of enzymes [9].
  • Although the role of PARP-1 in response to DNA damage has been studied extensively, the function of PARG and the impact of poly(ADP-ribose) homeostasis in various cellular processes are largely unknown [10].
  • This posttranslational modification is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG) [10].
  • The early cleavage of both PARP-1 and PARG by caspases during apoptosis suggests an important function for poly(ADP-ribose) metabolism regulation during this cell death process [11].
  • Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)-glycohydrolase (PARG); will this be a viable strategy for future drug design [12]?

Anatomical context of PARG

  • Human poly(ADP-ribose) glycohydrolase (PARG) gene and the common promoter sequence it shares with inner mitochondrial membrane translocase 23 (TIM23) [13].
  • In this study, we describe the construction of the first human PARG cDNA clone by reverse transcription of CF3 human fibroblast RNA [13].
  • Our findings suggest that shuttling of PARG between nucleus and cytoplasm and proper control of poly(ADP-ribose) metabolism throughout the cell cycle may play an important role in regulating cell cycle progression and centrosome duplication [14].
  • Finally, an interaction between immobilized PARG and endogenous PARP-1 from HeLa cell extracts is demonstrated [15].
  • Green fluorescent protein (GFP) fusion proteins were constructed for PARG (GFP-PARG), its 74 kDa (GFP-74) and 85 kDa (GFP-85) apoptotic fragments and transiently expressed in COS-7 cells [16].

Associations of PARG with chemical compounds

  • At present, only a single enzyme, poly (ADP-ribose) glycohydrolase (PARG), has been identified to catalyze ADP-ribose polymer hydrolysis in the cell causing a rapid turnover of the biopolymer which may ultimately result in lethal depletion of cellular NAD(+) pools [13].
  • We have found that inhibition of PARG by gallotannin (GT) (50 microM) provided significant cytoprotection to peroxynitrite- or hydrogen peroxide-treated HaCaT cells, as assessed by lactate dehydrogenase release and propidium iodide uptake (parameters of necrotic cell death) as well as caspase activation (apoptotic parameter) [17].
  • We conclude that neither GPI 16552 nor gallotannin are suitable for the evaluation of PARG in cellular death models, and that previous conclusions drawn from the use of these compounds should be interpreted with caution [18].
  • Human blood leukocytes generated large amounts of superoxide (O2-) following stimulation by certain "cocktails" of soluble agents consisting of poly-L-arginine (PARG), phytohemagglutinin, the chemotactic peptide formyl-methionyl-leucyl-phenylalanine and polyanethole sulfanote (liquoid) [19].
  • The transient decrease in the nuclear PARG activity by TPA treatment was accompanied by differentiation as measured by the nitroblue tetrazolium (NBT) reducing activity and adhesion to the culture dishes [20].

Physical interactions of PARG


Other interactions of PARG

  • In the present paper, we report that PARG is resident in FMRP (Fragile-X mental retardation protein)-associated messenger ribonucleoparticles complexes [9].
  • In summary, the potent inhibitory effects of GT on the transcription of cytokine and chemokine genes are probably not related to PARG inhibition [22].
  • In all extracts, a single PARG activity band corresponding to a protein of about 110 kDa was detected [23].
  • The activity of the promoter was found to be 3.7 fold higher for TIM23 than for PARG, indicating that the two genes are expressed at different levels, although coregulation of the two genes remains an interesting possibility [13].
  • All findings are consistent with the conclusion that ARH3 has PARG activity but is structurally unrelated to PARG [24].

Analytical, diagnostic and therapeutic context of PARG


  1. Poly(ADP-ribosyl)ation in relation to cancer and autoimmune disease. Masutani, M., Nakagama, H., Sugimura, T. Cell. Mol. Life Sci. (2005) [Pubmed]
  2. Role of poly(ADP-ribose) glycohydrolase (PARG) in shock, ischemia and reperfusion. Cuzzocrea, S., Wang, Z.Q. Pharmacol. Res. (2005) [Pubmed]
  3. Mediation of cell death by poly(ADP-ribose) polymerase-1. Koh, D.W., Dawson, T.M., Dawson, V.L. Pharmacol. Res. (2005) [Pubmed]
  4. Bile reflux in postoperative alkaline reflux gastritis. Cabrol, J., Navarro, X., Sancho, J., Simo-Deu, J., Segura, R. Ann. Surg. (1990) [Pubmed]
  5. A nonradiometric, high-throughput assay for poly(ADP-ribose) glycohydrolase (PARG): application to inhibitor identification and evaluation. Putt, K.S., Hergenrother, P.J. Anal. Biochem. (2004) [Pubmed]
  6. NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1. Kim, M.Y., Mauro, S., Gévry, N., Lis, J.T., Kraus, W.L. Cell (2004) [Pubmed]
  7. Poly(ADP-ribose) (PAR) polymer is a death signal. Andrabi, S.A., Kim, N.S., Yu, S.W., Wang, H., Koh, D.W., Sasaki, M., Klaus, J.A., Otsuka, T., Zhang, Z., Koehler, R.C., Hurn, P.D., Poirier, G.G., Dawson, V.L., Dawson, T.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase. Dumitriu, I.E., Voll, R.E., Kolowos, W., Gaipl, U.S., Heyder, P., Kalden, J.R., Herrmann, M. Cell Death Differ. (2004) [Pubmed]
  9. Poly(ADP-ribose) glycohydrolase is a component of the FMRP-associated messenger ribonucleoparticles. Gagné, J.P., Bonicalzi, M.E., Gagné, P., Ouellet, M.E., Hendzel, M.J., Poirier, G.G. Biochem. J. (2005) [Pubmed]
  10. Depletion of the 110-kilodalton isoform of poly(ADP-ribose) glycohydrolase increases sensitivity to genotoxic and endotoxic stress in mice. 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. Mol. Cell. Biol. (2004) [Pubmed]
  11. Caspase-3-mediated processing of poly(ADP-ribose) glycohydrolase during apoptosis. Affar, E.B., Germain, M., Winstall, E., Vodenicharov, M., Shah, R.G., Salvesen, G.S., Poirier, G.G. J. Biol. Chem. (2001) [Pubmed]
  12. Poly(ADP-ribose)polymerase inhibition - where now? Woon, E.C., Threadgill, M.D. Current medicinal chemistry. (2005) [Pubmed]
  13. Human poly(ADP-ribose) glycohydrolase (PARG) gene and the common promoter sequence it shares with inner mitochondrial membrane translocase 23 (TIM23). Meyer, R.G., Meyer-Ficca, M.L., Jacobson, E.L., Jacobson, M.K. Gene (2003) [Pubmed]
  14. Subcellular localization of poly(ADP-ribose) glycohydrolase in mammalian cells. Ohashi, S., Kanai, M., Hanai, S., Uchiumi, F., Maruta, H., Tanuma, S., Miwa, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  15. Tannins elevate the level of poly(ADP-ribose) in HeLa cell extracts. Keil, C., Petermann, E., Oei, S.L. Arch. Biochem. Biophys. (2004) [Pubmed]
  16. Alteration of poly(ADP-ribose) glycohydrolase nucleocytoplasmic shuttling characteristics upon cleavage by apoptotic proteases. Bonicalzi, M.E., Vodenicharov, M., Coulombe, M., Gagné, J.P., Poirier, G.G. Biol. Cell (2003) [Pubmed]
  17. Cytoprotective effect of gallotannin in oxidatively stressed HaCaT keratinocytes: the role of poly(ADP-ribose) metabolism. Bakondi, E., Bai, P., Erdélyi, K., Szabó, C., Gergely, P., Virág, L. Exp. Dermatol. (2004) [Pubmed]
  18. Poly(ADP-ribose) glycohydrolase as a target for neuroprotective intervention: assessment of currently available pharmacological tools. Falsig, J., Christiansen, S.H., Feuerhahn, S., Bürkle, A., Oei, S.L., Keil, C., Leist, M. Eur. J. Pharmacol. (2004) [Pubmed]
  19. NADPH and "cocktails" containing polyarginine reactivate superoxide generation in leukocytes lysed by membrane-damaging agents. Ginsburg, I., Borinski, R., Pabst, M. Inflammation (1985) [Pubmed]
  20. Changes in the activities and gene expressions of poly(ADP-ribose) glycohydrolases during the differentiation of human promyelocytic leukemia cell line HL-60. Uchiumi, F., Ikeda, D., Tanuma, S. Biochim. Biophys. Acta (2004) [Pubmed]
  21. MNNG-induced Cell Death Is Controlled by Interactions between PARP-1, Poly(ADP-ribose) Glycohydrolase, and XRCC1. Keil, C., Gr??be, T., Li Oei, S. J. Biol. Chem. (2006) [Pubmed]
  22. Gallotannin inhibits the expression of chemokines and inflammatory cytokines in A549 cells. Erdèlyi, K., Kiss, A., Bakondi, E., Bai, P., Szabó, C., Gergely, P., Erdödi, F., Virag, L. Mol. Pharmacol. (2005) [Pubmed]
  23. Poly(ADP-ribose) glycohydrolase is present and active in mammalian cells as a 110-kDa protein. Winstall, E., Affar, E.B., Shah, R., Bourassa, S., Scovassi, A.I., Poirier, G.G. Exp. Cell Res. (1999) [Pubmed]
  24. Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase. Oka, S., Kato, J., Moss, J. J. Biol. Chem. (2006) [Pubmed]
  25. Human poly(ADP-ribose) glycohydrolase is expressed in alternative splice variants yielding isoforms that localize to different cell compartments. Meyer-Ficca, M.L., Meyer, R.G., Coyle, D.L., Jacobson, E.L., Jacobson, M.K. Exp. Cell Res. (2004) [Pubmed]
  26. Poly(ADP-ribose) glycohydrolase in bovine retained and not retained placenta. Kankofer, M., Guz, L., Wierciński, J. Reprod. Domest. Anim. (2004) [Pubmed]
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