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)

Poly(ADP-ribose)polymerase (PARP)-activity was assessed in vitro from the incorporation of the adenosine-diphosphate-ribose moiety of 14C-NAD+ in the acid-insoluble cell fraction. When compared to mammalian (rat) cells, chicken embryo cells exhibit an almost three- to fourfold higher constitutive PARP-activity and an about two- to threefold lower chromatin compactness as evidenced by viscometry of alkaline cell lysates and nucleoid sedimentation. X-irradiation, bleomycin and H2O2 activated PARP. Hyperthermia (43 degrees C), doxorubicin, ethidium bromide and novobiocin resulted in an inhibition of the enzyme activity. Even at the highest doses used, UV-light, monofunctionally alkylating agents and the bisbenzimide Hoechst 33258 remained without significant effects. It is suggested that, with respect to DNA-and/or chromatin-interactive agents, the chicken embryo PARP-test may be complementary to the results of morphological and biochemical studies.
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PMID:Poly(ADP-ribose)polymerase-activity of chicken embryo cells exposed to nucleotoxic agents. 146 59

H2O2, in concentrations achieved in the proximity of stimulated leukocytes, induces injury and lysis of target cells. This may be an important aspect of inflammatory injury of tissues. Cell lysis in two target cells, the murine macrophage-like tumor cell line P388D1 and human peripheral lymphocytes, was found to be associated with activation of poly(ADP-ribose) polymerase (EC 2.4.2.30), a nuclear enzyme. This enzyme is activated under various conditions of DNA damage. Poly(ADP-ribose) polymerase utilizes nicotinamide adenine dinucleotide (NAD) as substrate and has been previously shown to consume NAD during exposure of cells to oxidants that was associated with inhibition of glycolysis, a decrease in cellular ATP, and cell death. In the current studies, inhibition of poly(ADP-ribose) polymerase by 3-aminobenzamide, nicotinamide, or theophylline in cells exposed to lethal concentrations of H2O2 prevented the sequence of events that eventually led to cell lysis--i.e., the decrease in NAD, followed by depletion of ATP, influx of extracellular Ca2+, actin polymerization and, finally, cell death. DNA damage, the initial stimulus for poly(ADP-ribose) polymerase activation, occurred despite the inhibition of this enzyme. Cells exposed to oxidant in the presence of the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide failed to demonstrate repair of DNA strand breaks.
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PMID:Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. 294 60

The influence of the nuclear ADP-ribosyltransferase inhibitor 3-aminobenzamide on the DNA strand-break rejoining kinetics and cytotoxicity in Chinese hamster ovary cells following H2O2 treatment was investigated. For the DNA damage studies, cells were treated on ice with H2O2 (0-20 microM) for 1 h in serum-free medium, after which the H2O2 was removed and the cells were allowed to repair their damage in complete medium at 37 degrees C in the presence or absence of 3-aminobenzamide (5 mM) for periods up to 2 h. The DNA strand breaks remaining as a function of time were then estimated by alkaline elution. A linear relationship between the H2O2 concentration and the initial level of DNA single-strand breaks (zero time allowed for repair) was observed. No double-strand breaks or DNA-protein cross-links were detected at these doses. The rejoining of single-strand breaks after H2O2 (20 microM) alone was characterized by a single exponential process with a t1/2 of approx. 5 min. However, in the presence of 3-aminobenzamide, rejoining was much slower and biphasic, with t1/2 of approx. 10 and 36 min. The inhibitory action of 3-aminobenzamide was concentration-dependent and completely reversible in that, when the 3-aminobenzamide was removed from the treated cultures, the strand-break rejoining kinetics rapidly returned to the t1/2 of 5 min typical of H2O2 alone. Considerably higher concentrations of H2O2 (up to 600 microM) were required for cell killing compared to the DNA damage studies. Cell killing by H2O2 alone was characterized by a shoulderless, exponential survival curve (D0 = 880 microM). The cytotoxicity was potentiated when the cells were treated with 3-aminobenzamide (5 mM) for 1 h after the H2O2 treatment; the survival curve with 3-aminobenzamide also assumed a biphasic character (D0 of 212 microM and 520 microM). These results are consistent with the theory that OH.-induced single-strand breaks do not normally represent lethal lesions to the cell because of their rapid, efficient repair. However, interference with these repair processes (in this case by 3-aminobenzamide) can alter this relationship, possibly allowing lesion fixation.
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PMID:Effect of 3-aminobenzamide on DNA strand-break rejoining and cytotoxicity in CHO cells treated with hydrogen peroxide. 371 90

We have recently described that poly(ADP-ribosyl)-polymerase (PARP) inhibitors rescue U937 cells from apoptosis induced by 1 mM H2O2 oxidative stress; PARP activation leads to a reversible drop in NAD level, which could be blocked by PARP inhibitors (Nos-seri et al., 1994, Exp. Cell Res. 212, 367-373). A phenotypic variant of U937 is characterized by a lower basal NAD level (low NAD, LN U937, as opposed to the original high NAD, HN U937). In LN cells treatment with 1 mM H2O2, although activating PARP, does not lower NAD concentration; puzzlingly, PARP inhibitors increase (instead of decreasing, as occurs in HN cells) the extent of stress-induced apoptosis, leading to a reduced cell survival. NAD concentration could be increased in LN cells by adding nicotinamide (5-and 25-fold increase) to the culture medium. These cells (LN+) behaved as HN U937: oxidative stress induced a NAD drop, the extent of which is dependent on the cells' basal NAD level; moreover, PARP inhibitors could rescue LN+ cells from peroxide-induced apoptosis. H2O2-induced apoptosis is not triggered by NAD depletion, but instead it takes place only when NAD levels have been preserved or have recovered: on HN U937, peroxide doses (5 and 10 mM) which lead to necrosis induce an irreversible NAD drop, whereas apoptosis occurs only at lower doses, where NAD depletion is reversible; on LN cells NAD levels do not drop even upon 10 mM H2O2 treatment, and these cells die only by apoptosis; moreover, in HN cells apoptosis is not detectable until 8 h posttreatment, when NAD levels recover, whereas in LN cells, where NAD is always present, apoptosis begins to take place as early as 3 h after stress.
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PMID:Different basal NAD levels determine opposite effects of poly(ADP-ribosyl)polymerase inhibitors on H2O2-induced apoptosis. 749 46

HN and LN are two phenotypic variants of the U937 monocytic cell line which differ in their basal NAD content; they respond in an opposite way to oxidative stress in the presence of the poly(ADP-ribosyl)polymerase (PARP) inhibitors 3-aminobenzamide (3ABA) and nicotinamide (NA): the inhibitors protect HN cells from stress-induced apoptosis, while they enhance it on LN cells (Coppola et al., 1995, Exp. Cell Res. 221, 462-469). These opposite effects are due to two overlapping and contrasting phenomena occurring in LN cells, as shown by the bi-modal response of stressed LN cells to increasing 3ABA doses. Indeed H2O2-induced apoptosis is enhanced only at high 3ABA concentrations (i.e., sufficient to inhibit also mono-ADP-ribosylations); lower 3ABA concentrations, which specifically inhibit PARP, also protect LN U937 from stress-induced apoptosis. Unlike HN U937, H2O2-induced apoptosis in LN cells is accompanied by cell blebbing. High 3ABA doses strongly enhance blebbing, leading to cellular fragmentation. Blebbing could be blocked by interfering with actin polymerization with cytochalasin B and D: this eliminated the increase in apoptosis due to 3ABA, suggesting that it is indeed the consequence of excess blebbing. This is supported by the unusual finding that in U937 LN stressed in the presence of 3ABA or NA, blebbing, usually a late event in apoptosis, may even precede its onset.
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PMID:The increase in H2O2-induced apoptosis by ADP-ribosylation inhibitors is related to cell blebbing. 749 47

Exposure to hydrogen peroxide (H2O2) decreases phosphatidylcholine (PC) synthesis in rabbit type II pneumocytes. Activation of poly(ADP-ribose) polymerase (PARP) may play a role in this process. Exposure of type II pneumocytes to H2O2 resulted in a 53% decrease in the rate of incorporation of [3H]choline into PC (P < 0.001). Cell NAD and ATP levels were decreased by 52% (P < 0.001) and 39% (P < 0.01), respectively, without significant changes in cell viability. Exposure to H2O2 also resulted in a 52% (P < 0.05) increase in the activity of PARP. Preincubation of type II cells with inhibitors of PARP (nicotinamide; 3-aminobenzamide) before H2O2 exposure prevented the increase in PARP activity, and blocked the decreases in ATP, NAD, and rate of PC synthesis. These results suggest that the energy depletion associated with activation of PARP contributes to the effects of oxidant stress on type II cell metabolic function and may be ameliorated by pharmacological agents in vitro.
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PMID:Inhibition of poly(ADP-ribose) polymerase preserves surfactant synthesis after hydrogen peroxide exposure. 763 15

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which catalyzes the transfer of ADP-ribose units from NAD+ to a variety of nuclear proteins under the stimulation of DNA strand break. To examine its role in DNA repair, we have been studying the interaction of PARP with other nuclear proteins using disulfide cross-linking, initiated by sodium tetrathionate (NaTT). Chinese Hamster Ovary (CHO) cells were extracted sequentially with Nonidet P40 (detergent), nucleases (DNase+RNase), and high salt (1.6 M NaCl) with and without the addition of a sulfhydryl reducing agent. The residual structures are referred to as the nuclear matrix, and are implicated in the organization of DNA repair and replication. Treatment of the cells with NaTT causes the crosslinking of PARP to the nuclear matrix. Activating PARP by pretreating the cells with H2O2 did not increase the cross-linking of PARP with the nuclear matrix, suggesting a lack of additional interaction of the enzyme with the nuclear matrix during DNA repair. Both NaTT and H2O2 induced crosslinks of PARP that were extractable with high salt. To shorten the procedure, these crosslinks were extracted from cells without nucleases and high salt treatment, using phosphate buffer. Using western blotting, these crosslinks appeared as a smear of high molecular weight species including a possible dimer of PARP at 230 kDa, which return to 116 kDa following reduction with beta-mercaptoethanol.
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PMID:Association of poly(ADP-ribose) polymerase with nuclear subfractions catalyzed with sodium tetrathionate and hydrogene peroxide crosslinks. 885 66

Persistent hepadnavirus infection leads to oxidative stress and DNA damage through increased production of toxic oxygen radicals. In addition, hepadnaviral DNA integrations into chromosomal DNA can promote the process of hepatocarcinogenesis (M. Feitelson, Clin. Microbiol. Rev. 5:275-301, 1992). While previous studies have identified preferred integration sites in hepadnaviral genomes and suggested integration mechanisms (M. A. Buendia, Adv. Cancer Res. 59:167-226, 1992; C. E. Rogler, Curr. Top. Microbiol. Immunol. 168:103-141, 1991; C. Shih et al., J. Virol. 61:3491-3498, 1987), very little is known about the effects of agents which damage chromosomal DNA on the frequency of hepadnaviral DNA integrations. Using a recently developed subcloning approach to detect stable new integrations of duck hepatitis B virus (DHBV) (S. S. Gong, A. D. Jensen, and C. E. Rogler, J. Virol. 70:2000-2007, 1996), we tested the effects of increased chromosomal DNA damage induced by H2O2, or of the disturbance in DNA repair due to the inhibition of poly(ADP-ribose) polymerase (PARP), on the frequency of DHBV DNA integrations. Subclones of LMH-D21-6 cells, which replicate DHBV, were grown in the presence of various H2O2 concentrations and exhibited up to a threefold increase in viral DNA integration frequency in a dose-dependent manner. Moreover, inhibition of PARP, which plays a role in cellular responses to DNA breakage, by 3-aminobenzamide (3-AB) resulted in a sevenfold increase in the total number of new DHBV DNA integrations into host chromosomal DNA. Removal of either H2O2 or 3-AB from the culture medium in a subsequent cycle of subcloning was accompanied by a reversion back towards the original lower frequency of stable DHBV DNA integrations for LMH-D21-6 cells. These data support the hypothesis that DNA damage sites can serve as sites for hepadnaviral DNA integration, and that increasing the number of DNA damage sites dramatically increases viral integration frequency.
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PMID:Increase in the frequency of hepadnavirus DNA integrations by oxidative DNA damage and inhibition of DNA repair. 918 18

The importance of a genetic polymorphism (A/B allele) of poly(ADP-ribose) polymerase (PARP) pseudogene on chromosome 13q34-qter, and PARP enzyme activities in the development of human breast cancer were evaluated in a cancer case-control study. A total of 309 Caucasian women (> or = 50 years old) were evaluated for the PARP genotype, 70 of whom had histologically confirmed breast cancer, 128 women with benign breast diseases as study controls, and 111 reference controls. Age was significantly associated with case-control status (p < 0.0001), but family history of breast cancer, age at menarche, age at first live birth and parity were not. The frequency of the PARP B allele was similar in breast cancer cases (0.14), study controls (0.13), and reference controls (0.15). In a subset of 14 breast cancer cases and 32 study controls, the mean PARP enzyme activities (induced by H2O2 or oligonucleotide) were observed to be lower in cancer cases; an age-adjusted odds ratio of 3.40 (95% confidence interval = 0.70-19.54) for the below-median oligonucleotide-induced PARP was suggestive of an association. In subjects with the AB or BB genotype, the mean H2O2-induced PARP enzyme activity was significantly higher (p = 0.02, adjusted for case-control status and age) compared with that in subjects with the AA genotype. These findings indicate that: (a) the genetic polymorphism of the PARP pseudogene on chromosome 13 is not associated with the development of breast cancer in our study population; (b) oligonucleotide-induced PARP activity may be useful for identifying postmenopausal women at increased risk for breast cancer; and (c) there is a possible functional link between the genotype of the PARP pseudogene and enzyme activation.
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PMID:Poly(ADP-ribose) polymerase in human breast cancer: a case-control analysis. 929 59

Four volunteers were involved for 5 weeks of a baseline period, followed by 7 weeks of a combined supplementation of nicotinamide, zinc, and carotenoids (Nicoplex). Blood sampling and bioassays were carried out every week during the evaluation period. The supplementation of Nicoplex resulted in statistically significant increased resistance to DNA single-strand breaks induced by H2O2 (DNA retained on filter % from 46.7 +/- 1.9 to 59.4 +/- 4.3; p < 0.01), increased DNA repair 60 min after induction of damage (DNA retained on filter % from 74.6 +/- 4.8 to 88.3 +/- 4.2; p < 0.01), elevated poly (ADP-ribose) polymerase (PARP) activity (p < 0.05), and an increased proliferative response to phytohemagglutinin (PHA) (p < 0.05) when compared with the levels before supplementation. However, when the same subjects were supplemented with nicotinamide, zinc, and carotenoids together with another 17 nutrients or minerals, there were no changes in DNA damage, DNA repair, or proliferative response to PHA. Through the use of a rat model, DNA repair of splenocytes 3 h after 12 Gy whole-body irradiation was significantly enhanced in rats supplemented with Nicoplex for 6 weeks (p < 0.05) and 8 weeks (p < 0.01). Comparison of Nicoplex and its components administered separately revealed that there was an additive effect on DNA repair for both single- and double-strand breaks (both p < 0.05). On the basis of the results, it is hypothesized that the enhanced effect of combined supplement of nicotinamide, zinc, and carotenoids on DNA repair depends on their diversified mechanisms of action while multinutrient supplementation may compromise the effects by inhibitory interactions including uptake and absorption.
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PMID:DNA repair enhancement by a combined supplement of carotenoids, nicotinamide, and zinc. 967 71


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