Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In plants many biotic and abiotic stresses can cause secondary oxidative stress. Earlier work showed that, depending on the severity of the oxidative stress, plants can activate either cell protective genes or programmed cell death (PCD). Poly(ADP-ribose) polymerase (PARP) has been implicated as one of the enzymes in the apoptotic pathways induced by DNA damaging agents or oxidative stress. We show that in cultured soybean cells, PARP is involved in responses to mild and severe oxidative stresses, by mediating DNA repair and PCD processes, respectively. Addition of PARP inhibitors reduced the degree of cell death triggered by H2O2. Two windows of NAD consumption after H2O2 treatment were detected. Experiments with transient overexpression of Arabidopsis PARP cDNA promoted DNA repair and inhibited cell death caused by mild oxidative stress. However, following severe stress PARP overexpression increased cell death. Expression of antisense PARP produced the opposite effects: an increase in DNA nicks and inhibition of cell death at high, but not mild doses of H2O2.
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PMID:The involvement of poly(ADP-ribose) polymerase in the oxidative stress responses in plants. 986 13

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that recognizes and binds to the nicks and ends of DNA, and catalyses successive ADP-ribosylation reactions. To clarify the function of PARP at the molecular level, we searched proteins which interact with PARP. In the auto-modification domain of PARP in Drosophila, there is a putative leucine-zipper motif which can interact with other protein molecules. To find interacting proteins we examined the auto-modification domain of Drosophila PARP, using the Far-Western screening method. From six independent cDNA clones isolated, we characterized two clones, PBP-3 and PBP-12. The predicted amino acid sequences from 109 to 269 of PBP-3 and from 184 to 312 of PBP-12 had more than 62% identities to mammalian L23a (rpl23a) and L22 (rpl22), the ribosomal proteins of the large subunit. This indicated that PBP-3 and PBP-12 are Drosophila homologues of L23a and L22, respectively. These Drosophila ribosomal protein L22 and L23a have additional Ala-, Lys- and Pro-rich sequences at the amino terminus, which have a resemblance to the carboxy-terminal portion of histone H1. Thus, Drosophila L22 and L23a might have two functions, namely the role of DNA-binding similar to histone H1 and the role of organizing the ribosome.
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PMID:Poly(ADP-ribose) polymerase interacts with novel Drosophila ribosomal proteins, L22 and l23a, with unique histone-like amino-terminal extensions. 993 8

Poly(ADP-ribose) polymerase (PARP) is a constitutive factor of the DNA damage surveillance network in dividing cells. Based on its capacity to bind to DNA strand breaks, PARP plays a regulatory role in their resolution in vivo. ATM belongs to a large family of proteins involved in cell cycle progression and checkpoints in response to DNA damage. Both proteins may act as sensors of DNA damage to induce multiple signalling pathways leading to activation of cell cycle checkpoints and DNA repair. To determine a possible relationship between PARP and ATM, we examined the PARP response in an ATM-null background. We demonstrated that ATM deficiency does not affect PARP activity in human cell lines or Atm-deficient mouse tissues, nor does it alter PARP activity induced by oxidative damage or gamma-irradiation. Our results support a model in which PARP and ATM could be involved in distinct pathways, both effectors transducing the damage signal to cell cycle regulators.
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PMID:Poly(ADP-ribose) polymerase activity is not affected in ataxia telangiectasia cells and knockout mice. 993 67

Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD+ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP -/-), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP +/- animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.
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PMID:Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. 1007 36

Poly(ADP-ribose) polymerase (PARP) and DNA-dependent protein kinase (DNA-PK) are important nuclear enzymes that cooperate to minimize genomic damage caused by DNA strand interruptions. DNA strand interruptions trigger the ADP-ribosylation activity and phosphorylation activity of PARP and DNA-PK respectively. In order to understand the relationship of PARP and DNA-PK with respect to DNA binding required for their activation, we analyzed the kinetics of the reactions and determined the apparent dissociation constants (Kd app) of the enzymes for DNA strand interruptions. PARP has a high binding affinity for blunt ends of DNA (Kd app=116 pM) and 3' single-base overhangs (Kd app=332 pM) in comparison to long overhangs (Kd app=2.6-5.0 nM). Nicks are good activators of PARP although the affinity of PARP for nicks (Kd app=467 pM) is 4-fold less than that for blunt ends. The Kd app of DNA-PK for 3' single-base overhangs, blunt ends and long overhangs is 704 pM, 1.3 nM and 1.4-2.2 nM respectively. These results demonstrate that (1) PARP, when compared to DNA-PK, has a greater preference for blunt ends and 3' single-base overhangs but a weaker preference for long overhangs, and (2) nicks are effective in attracting and activating PARP. The possible implications of the preferences of PARP and DNA-PK for DNA strand interruptions in vivo are discussed.
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PMID:Relative affinities of poly(ADP-ribose) polymerase and DNA-dependent protein kinase for DNA strand interruptions. 1008 40

Poly(ADP-ribose) polymerase (PARP) activity is widespread among eukaryotes. Upon DNA damage PARP binds to DNA strand breaks and transfers ADP-ribose residues from NAD+ to acceptor proteins and to ADP-ribosyl protein adducts. This leads to branched polymers of protein-coupled poly(ADP-ribose) (pADPr). Because the germline of Drosophila has recently become important in the study of DNA double-strand break repair (DSBR) as opposed to somatic DSBR we tested whether the catalytic activity of PARP can be stimulated by gamma-irradiation during Drosophila spermatogenesis. Using antibodies against pADPr we detected a significant increase in PARP activity in male germline cells during spermatogenesis upon gamma-irradiation. Different stages of spermatogenesis revealed different subnuclear localization patterns of pADPr. In premeiotic and postmeiotic cells pADPr localized in a pattern overlapping with lamin and topoisomerase II at the nuclear rim. In primary spermatocytes pADPr is associated with three loci corresponding to the chromosomes at the nuclear periphery.
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PMID:Detection of poly(ADP-ribose) synthesis in Drosophila testes upon gamma-irradiation. 1019 55

Poly(ADP-ribose) polymerase (PARP) is a zinc-finger DNA binding protein that detects and signals DNA strand breaks generated directly or indirectly by genotoxic agents. In response to these lesions, the immediate poly(ADP-ribosylation) of nuclear proteins converts DNA interruptions into intracellular signals that activate DNA repair or cell death programs. To elucidate the biological function of PARP in vivo, the mouse PARP gene was inactivated by homologous recombination to generate mice lacking a functional PARP gene. PARP knockout mice and the derived mouse embryonic fibroblasts (MEFs) were acutely sensitive to monofunctional alkylating agents and gamma-irradiation demonstrating that PARP is involved in recovery from DNA damage that triggers the base excision repair (BER) process. To address the issue of the role of PARP in BER, the ability of PARP-deficient mammalian cell extracts to repair a single abasic site present on a circular duplex plasmid molecule was tested in a standard in vitro repair assay. The results clearly demonstrate, for the first time, the involvement of PARP in the DNA synthesis step of the base excision repair process.
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PMID:Involvement of poly(ADP-ribose) polymerase in base excision repair. 1021 12

Poly(ADP-ribose) polymerase (PARP) is conserved in eukaryotes. To analyze the function of PARP, we isolated and characterized the gene for PARP in Drosophila melanogaster. The PARP gene consisted of six translatable exons and spanned more than 50 kb. The DNA binding domain is encoded by exons 1-4. Although the consensus cleavage site of CED-3 like protease during apoptosis is conserved from human to Xenopus laevis PARPs, it is neither conserved in the corresponding region of Drosophila nor Sarcophaga peregrina. There are two cDNAs species in Drosophila. One cDNA could encode the full length PARP protein (PARP I), while the other is a truncated cDNA which could encode a partial-length PARP protein (PARP II), which lacks the automodification domain and is possibly produced by alternative splicing. The expression of these two forms of PARP in E. coli demonstrated that while PARP II has the catalytic NAD-binding domain and DNA-binding domain it is enzymatically inactive. On the other hand PARP I is active. A deletion mutant of PARP gene could grow to the end of embryogenesis but did not grow to the adult fly. These results suggest that the PARP gene plays an important function during the development of Drosophila.
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PMID:Functional analysis of poly(ADP-ribose) polymerase in Drosophila melanogaster. 1033 45

Poly(ADP-ribose) polymerase (PARP) is thought to play a physio-logical role in maintaining genomic integrity and in the repair of DNA strand breaks. However, the activation of PARP by free radical-damaged DNA plays a pivotal role in mediating ischemia-reperfusion injury. The excessive activation of PARP causes a rapid depletion of intracellular energy leading to cell death. The present study examined the effect of post-ischemic pharmacological inhibition of PARP in a rat focal cerebral ischemia model. In Long-Evans rats, focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid artery (CCA) occlusion for 90 min. A PARP inhibitor, 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ; IC50=1 microM/l) was injected i.p. 30 min after the onset of MCA occlusion (control: 10, 20, 40 and 80 mg/kg; n=7 each). Twenty-four hours later, the total infarct volume was measured. Regional blood flow in the right parietal cortex decreased to approximately 20% of the baseline following MCA occlusion in all groups. PARP inhibition lead to a significant decrease in damaged volume in all treated groups with the largest reduction in the 40 mg/kg group (111.5+/-24. 8 mm3, mean+/-SD, p<0.01), compared to the control group (193.5+/-28. 6 mm3). We also found there was a significant increase of poly(ADP-ribose) immunoreactivity in the ischemic region, as compared to the contralateral side, with DPQ treatment diminishing poly(ADP-ribose) production. These findings indicate that DPQ exerts its neuroprotective effects in vivo by PARP inhibition and that PARP inhibitors may be effective for treating ischemic stroke, even when the treatment is initiated after the onset of ischemia.
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PMID:Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia. 1035 May 29

Poly(ADP-ribosylation) is a post-translational modification of nuclear proteins in response to DNA damage that activates the base excision repair machinery. Poly(ADP-ribose) polymerase which we will now call PARP-1, has been the only known enzyme of this type for over 30 years. Here, we describe a cDNA encoding a 62-kDa protein that shares considerable homology with the catalytic domain of PARP-1 and also contains a basic DNA-binding domain. We propose to call this enzyme poly(ADP-ribose) polymerase 2 (PARP-2). The PARP-2 gene maps to chromosome 14C1 and 14q11.2 in mouse and human, respectively. Purified recombinant mouse PARP-2 is a damaged DNA-binding protein in vitro and catalyzes the formation of poly(ADP-ribose) polymers in a DNA-dependent manner. PARP-2 displays automodification properties similar to PARP-1. The protein is localized in the nucleus in vivo and may account for the residual poly(ADP-ribose) synthesis observed in PARP-1-deficient cells, treated with alkylating agents or hydrogen peroxide.
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PMID:PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. 1036 31


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