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At least 19 recordsLinked to original sources
PubMed1979

Intrinsic ADP-ribose transferase activity versus levels of mono(adp-ribose)protein conjugates in proliferating Ehrlich ascites tumor cells.

Transition of proliferating Ehrlich ascites tumor cells (3 days after transplantation) to the non-proliferating status (8--14 days after transplantation) was associated with an increase in total mono (ADP-ribose) protein conjugates. This increase was largely confined to the NH2OH-resistant subfraction. When the amounts of mono-(ADP-ribose) conjugates from 20% trichloroacetic acid precipitates were compared with those from 5% perchloric acid precipitates, no significant differences were seen. This fact excludes histone H1 as a major mono (ADP-ribose) acceptor in vivo in these cells. Transition to the resting state was also associated with a small decrease in NAD levels, and with no significant changes of total ADP-ribose transferase activity. However intrinsic ADP-ribose transferase activity as expressed in permeabilized cells was increased, being correlated with the changes in the level of the NH2OH-resistant mono (ADP-ribose) protein conjugates. This shows that alterations in intrinsic transferase activity may, in general, indicate similar alterations in major subfractions of ADP-ribose conjugates. Intrinsic ADP-ribose transferase activity exhibited an inverse relationship to ornithine decarboxylase activity.

Adenosine Diphosphate Ribose↗
PubMed1993

ADP-ribosylation of neurofilaments by a cytoplasmic ADP-ribose transferase associated with free mRNP.

ADP-ribosylation of neurofilaments by an ADP-ribose transferase isolated from cytoplasmic ribonucleoprotein particles is demonstrated. The 150 kDa neurofilament subunit appears to be the main ADP-ribose acceptor with the transfer of ADP-ribose dimers or monomers. A binding of about 1 mole ADP-ribose per 8 moles of neurofilament subunits has been recorded. An interaction between neurofilaments' ADP-ribosylation and their phosphorylation state is demonstrated.

Adenosine Diphosphate Ribose↗
PubMed1991

Destabilization of Zn2+ coordination in ADP-ribose transferase (polymerizing) by 6-nitroso-1,2-benzopyrone coincidental with inactivation of the polymerase but not the DNA binding function.

6-Nitroso-1,2-benzopyrone, an oxidation product of 6-amino-1,2-benzopyrone, binds to the DNA-recognizing domain of the ADP-ribose transferase protein and preferentially destabilizes Zn2+ from one of the two zinc finger polypeptide complexes present in the intact enzyme, as determined by the loss of 50% of 65Zn2+ from the 65Zn(2+)-isolated protein molecule, coincidental with the loss of 99% of enzymatic activity. The 50% zinc-deficient enzyme still binds to a DNA template, consisting of a 17-mer DNA primer annealed to M13 positive strand, resulting in the blocking of DNA synthesis by the Klenow fragment of Pol I. Auto-poly-ADP-ribosylated ADP-ribose transferase, which is the probable physiological state of this protein in intact cells, does not bind to primer-template DNA and does not block DNA synthesis by the Klenow fragment. On the basis of this in vitro model it is proposed that molecules which inhibit or inactivate ADP-ribose transferase in intact cells can induce significant alteration in DNA structure and replication.

Base Sequence↗
PubMed1984

Regulation of poly(ADP-ribose) transferase activity by 2',5'-oligoadenylates.

pppA2'pA2'pA appears to be a potent natural noncompetitive inhibitor of poly (ADP-ribose) transferase activity in the histone dependent reaction of ADP-ribosylation with Ki=5 microM. Moreover, it is a noncompetitive inhibitor of the Mg2+ dependent reaction of autoADPRT-ribosylation with Ki=20 microM. The activity of ADPRT falls down abruptly both in the cytoplasm and nuclei of mouse L-cells treated with interferon. In contrast, the activities of 2',5'-oligo (A) polymerase and 2'-phosphodiesterase remain virtually unchanged after the treatment with ADPRT preparation. The regulation of ADPRT activity and active form of ADPRT by 2',5-oligoadenylates is presumed to be one of the factors responsible for inducing the antiviral and/or antiproliferative effects of interferon.

Adenine Nucleotides↗
PubMed1988

Differential radiosensitization by the poly(ADP-ribose) transferase inhibitor 3-aminobenzamide in human tumor cells of varying radiosensitivity.

Four newly-established human tumor cell lines, have been irradiated at dose rates of 150 and 3.2 cGy/min to compare their capacity to repair radiation damage. They included a neuroblastoma, a germ-cell carcinoma of the testis, a large cell carcinoma of the lung, and a carcinoma of the cervix. The four lines varied in their sensitivity to high dose-rate irradiation, with the neuroblastoma being most radiosensitive and the lung and cervix tumors the most radioresistant. The extent of dose sparing associated with lowering the dose rate to 3.2 cGy/min was similar in three of the lines but somewhat greater in the case of the cervix carcinoma cell line. The presence of non-toxic concentrations of the poly(ADP-ribose) transferase inhibitor, 3-aminobenzamide (3-AB), enhanced the response of 3 of the 4 tumors to irradiation; it failed to modify the sensitivity of a lung carcinoma cell line. The extent of sensitization was generally similar at high and low dose rate. Measurement of poly(ADP-ribose) transferase activity in control and irradiated cells showed the neuroblastoma cells to contain much higher initial levels than the other three lines but there were no significant differences in the extent of stimulation in enzyme levels after irradiation. Survival curves obtained at low dose-rate help define the initial slope of the acute curve and it appears that 3-AB may exert a differential effect among human tumors in modifying this component.

Benzamides↗
PubMed1987

Analogues of benzamide containing a sulfur atom as poly(ADP-ribose) transferase inhibitors.

Structural analogues of benzamide (BA) containing a sulfur atom were tested for their ability to inhibit the enzyme poly(ADP-ribose)transferase (ADPRT) in cultured Chinese Hamster Ovary (CHO) cells. These compounds were benzene sulfonamide (BSA), thiobenzamide (TB) and 3-thiophene carboxamide (TCA) and their activity was compared with that of benzamide in a number of experimental systems. Results have shown that substitution of the carboxamide function with a sulfonamide group produces an almost complete loss of the enzyme inhibiting activity. Also inactive was TB which however was found to display inhibition of the DNA damaging effect of hydrogen peroxide, thus suggesting a hydroxyl radical scavenging effect of TB. TCA, an isostere of BA, produced some inhibition of ADPRT, although its activity was markedly lower than that of the parental drug. Therefore, these results indicate that: 1) ADPRT inhibiting activity is inverse function of dipole moments, hydrogen bonding strength and steric hindrance of the amide functional group and 2) substitution of benzene with thiophene results in a substantial reduction of the enzyme inhibiting activity.

Animals↗
PubMed1990

Inhibitor of poly(ADP-ribose)transferase potentiates the recombinogenic but not the mutagenic action of alkylating agents in somatic cells in vivo in Drosophila melanogaster.

The effect on somatic mutations and recombination by 3-aminobenzamide (3-ABA), an inhibitor of poly(ADP-ribose) transferase, was studied in the somatic wing spot test in Drosophila melanogaster, 3-ABA did not exert any effect by itself, but caused a strong increase of wing spots in combination with methyl methanesulphonate (MMS) and ethylnitrosourea (ENU). MMS and ENU differ in their mutagenic effects, ENU causing a much higher frequency of point mutations than MMS. The enhancement by 3-ABA of chemically induced wing spots was totally eliminated by the introduction of a heterozygous inversion. It can be concluded that 3-ABA interacted with the chemical mutagens for the induction of somatic recombination, but had no effect on point mutations or intragenic events.

Alkylating Agents↗
PubMed1999

Cleavage of poly(ADP-ribose) transferase during p53-independent apoptosis in rat liver after treatment with N-nitrosomorpholine and cyproterone acetate.

The aim of this work was to study the role of the tumor suppressor p53 and of poly(ADP-ribose) transferase (pADPRT) in the control of hepatocyte apoptosis in two different in vivo models, i.e., during the process of tumor initiation by the genotoxin and cytotoxin N-nitrosomorpholine (NNM) and after withdrawal of the hepatomitogen cyproterone acetate (CPA). Treatment with NNM induces apoptosis followed by necrosis and regenerative DNA synthesis. At the first wave of apoptosis 12 h after NNM application, no p53 expression could be detected by immunohistochemical analysis and immunoblotting. However, 24 h after treatment, numerous p53-positive hepatocyte nuclei were detected, whereas hepatocytes in early and later stages of apoptosis were always negative. Simultaneously with the increased p53 levels, p21 protein was induced. This was accompanied by a block in replicative DNA synthesis, as detected by proliferating-cell nuclear antigen immunostaining. Concomitantly with the increase in apoptosis, dramatic degradation of the nuclear enzyme pADPRT was observed, as evidenced by immunoblotting and activity blotting. The decrease in pADPRT enzymatic activity observed 12 h after treatment coincided with the greatest extent of pADPRT cleavage. One prominent cleavage product was 64 kDa, suggesting that granzyme B was involved in pADPRT degradation. In the second in vivo model we used, i.e., withdrawal of treatment with the hepatomitogen CPA, apoptosis of excessive hepatocytes but no necrosis occurs. Again, no induction of p53 expression could be detected in the liver even at the maximum level of apoptosis, whereas a strong correlation between induction of apoptosis and cleavage of pADPRT to a 64-kDa fragment was observed. These results from whole-animal experiments strongly suggest that the induction of apoptosis in rat liver after genotoxic and cytotoxic damage and during regression of hyperplasia is driven by a p53-independent pathway but is accompanied by cleavage of pADPRT.

Animals↗
PubMed1986

Chilling followed by incubation at 37 degrees C causes a reduction in NAD+ levels which can be prevented by the poly(ADP-ribose)transferase inhibitor 3-aminobenzamide.

The exposure of cells for 60 min to a serum free medium at ice temperature followed by a return to normal culture conditions (30 min at 37 degrees C) caused a dramatic decrease in NAD+ levels. This decrease in NAD+ was prevented by 3-aminobenzamide. Alkaline elution analysis of DNA from cultures that were sisters to the ones utilized for measuring cellular NAD+ content revealed an absence of DNA breakage. These data suggest that poly(ADP-ribose)transferase may be induced in conditions not involving DNA fragmentation. The induction of this enzyme could therefore represent a cellular emergency reaction and not just a response to DNA damage.

Animals↗
PubMed1994

Poly(ADP-ribose) catabolism in mammalian cells.

Poly(ADP-ribose) catabolism is a complex situation involving many proteins and DNA. We have developed an in vitro turnover system where poly(ADP-ribose) metabolism is monitored in presence of different relative amounts of two principal enzymes poly(ADP-ribose) transferase and poly(ADP-ribose) glycohydrolase along with other proteins and DNA. Our current results reviewed here show that the quality of polymer, i.e. chain length and complexity, as well as preference for the nuclear substrate varies depending upon the availability of poly(ADP-ribose) glycohydrolase. These results are interpreted in the light of the recent data implicating poly(ADP-ribose) metabolism in DNA-repair.

DNA Polymerase II↗
PubMed1985

Benzamide on chondrocytic differentiation in chick limb bud cell culture.

Benzamide, an inhibitor of (ADP-ribose) transferase, augmented chondrocytic differentiation of chick limb bud mesenchymal cells in micromass cultures; the incorporation of 35SO4(2-) into the trichloroacetic-acid-insoluble constituents of cell masses as well as the formation of cartilage nodules (Nishio, Nakanishi, Doull & Uyeki, 1983) occurred about 24 h earlier than in untreated cultures and continued to be enhanced in benzamide-treated cultures of stage 23- to 24-chick limb bud cells. Benzamide also significantly increased cell proliferation. However, benzamide did not affect DNA and RNA syntheses except for one period: 24 to 30 h after the start of culture, RNA synthesis was stimulated. From 48 h of culture, (ADP-ribose) transferase activity decreased daily in untreated cultures, whereas benzamide treatment diminished (ADP-ribose) transferase activity 24 h earlier. On the other hand, intracellular NAD levels increased daily in untreated cultures, and benzamide significantly increased the NAD levels above untreated cultures. ATP levels did not differ significantly during the culture period, and benzamide did not affect ATP levels.

Adenosine Triphosphate↗
PubMed1980

ADP-ribosylation of nuclear proteins in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells.

Normal lymphocytes and lymphocytes from patients with low-grade malignant non-Hodgkin lymphoma were isolated from blood by a Percoll gradient procedure. Absence of cell proliferation in both cell types was indicated by very low [3H]thymidine incorporation rates. Determination of endogenous protein-bound single ADP-ribose residues by a radioimmunoassay revealed that the leukemic cells had 2.5-times lower levels of the NH2OH-sensitive and a 4-fold lower amount of NH2OH-resistant ADP-ribose . protein conjugate subfractions, respectively, than normal lymphocytes. By contrast, "total" ADP-ribose transferase activity, as measured in homogenates or permeabilized cells in the presence of DNase, was two-times higher in leukemic cells, whereas activity determined in permeabilized cells in the absence of added DNase was practically identical in both cell types. The apparent discrepancy between ADP-ribose transferase activity and endogenous levels of protein-bound single ADP-ribose residues may be explained in part by an enzyme inhibitor present in normal human lymphocytes. NAD + NADH levels were decreased 2.5-fold in the leukemic cells. This decrease, however, does not explain the reduced levels of mono(ADP-ribose) . protein conjugates since the ratio of protein-bound single ADP-ribose residues to NAD is distinctly different in leukemic lymphocytes compared to normal lymphocytes.

ADP Ribose Transferases↗
PubMed1986

Chromium effects on chondrocytic differentiation in vitro.

A tissue culture study was conducted on the effects of chromium on chondrocytic differentiation. Mesenchymal cells from stage 22-24 chick limb buds were dispersed and cultured as micromasses, where they differentiated into chondrocytes. Addition of chromium(VI) to the cultures indicated that the production of proteoglycans (as detected by Alcian blue staining) was more sensitive to chromium's effects than was cell proliferation. Whereas Alcian blue nodule formation was inhibited by 1 microM Cr(VI), cell proliferation (as detected by cell counts) was not. Chromium (VI) was added to cultures at daily intervals, and these studies indicated that the interval of d 1-2 was the most sensitive period. ADP-ribose transferase activity in these cultures was measured; the pattern of enzyme activity in control cultures was high 1 and 24 h after the start of culture, decreased abruptly between 24 and 48 h, and then decreased more gradually. In the presence of Cr(VI), elevated ADP-ribose transferase levels were maintained throughout the culture period. We suggest that, in presence of 1.0 microM chromium(VI) or higher concentrations, the balance of events favors nucleolytic action rather than repair of damage.

Alcian Blue↗
PubMed1992

Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase.

Two classes of enzymes, poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferases, catalyze covalent attachment of multiple or single residues, respectively, of the ADP-ribose moiety of NAD+ to various proteins. In order to find good inhibitors of poly(ADP-ribose) synthetase free of side actions and applicable to in vivo studies, we made a large scale survey using an in vitro assay system, and found many potent inhibitors. The four strongest were 4-amino-1,8-naphthalimide, 6(5H)- and 2-nitro-6(5H)-phenanthridinones, and 1,5-dihydroxyisoquinoline. Their 50% inhibitory concentrations, 0.18-0.39 microM, were about two orders of magnitude lower than that of 3-aminobenzamide that is currently most popularly used. A common structural feature among all potent inhibitors, including 1-hydroxyisoquinoline, chlorthenoxazin, 3-hydroxybenzamide, and 4-hydroxyquinazoline, in addition to the four mentioned above, was the presence of a carbonyl group built in a polyaromatic heterocyclic skeleton or a carbamoyl group attached to an aromatic ring. Most of the inhibitors exhibited mixed-type inhibition with respect to NAD+. Comparative studies of the effects on poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase from hen heterophils revealed high specificity of most of the potent inhibitors for poly(ADP-ribose) synthetase. On the other hand, unsaturated long-chain fatty acids inhibited both enzymes, and saturated long-chain fatty acids and vitamin K1 acted selectively on mono(ADP-ribosyl)transferase. The finding of many inhibitors of ADP-ribosyltransferases, especially poly(ADP-ribose) synthetase, supports the view that ADP-ribosylation of proteins may be regulated by a variety of metabolites or structural constituents in the cell.

ADP Ribose Transferases↗
PubMed1980

Adenosine diphosphate ribose transferase from baby-hamster kidney cells (BHK-21/C13). Characterization of the reaction and product.

Some properties of ADP-ribose transferase, and its reaction product, from BHK-21/C13 cells are described. Enzyme activity was found almost exclusively in nuclei (90%), with the remaining 10% located in the cytosolic fraction. The nuclear enzyme is chromatin-bound and requires bivalent cations, preferably Mg2+, a pH of 8.0 and a temperature of 25 degrees C for optimal activity. Chromatin preparations incorporated radioactivity from [14C]NAD+ into acid-insoluble material for about 60 min. Kinetics for substrate NAD+ utilization were not of Michaelis--Menten type; biphasic kinetics were shown from a double-reciprocal plot (1/reaction velocity against 1/[NAD+]) and from a 'Hofstee' plot (reaction velocity/[NAD+] against reaction velocity). The transferase is unstable in the absence of Mg2+ ions. It is inhibited by thymidine, nicotinamide and nicotinamide analogues, but not by ATP, which stimulates it at concentrations of 5 mM and above. The enzyme requires thiol groups for activity; it is readily inhibited by N-ethylmaleimide at 0.5 mM. The product of the reaction is stable under acid conditions at temperatures up to 25 degrees C, but it is hydrolysed by HClO4 at 70 degrees C. It is resistant to NaOH, but is cleaved from its attachment to protein with alkali into trichloroacetic acid-insoluble and -soluble components. On the basis of Cs2SO4- density-gradient analysis under denaturing conditions (gradients included urea and guanidinium hydrochloride), and analysis of the reaction product directly on hydroxyapatite, we conclude that most of the radioactive ADP-ribose residues are firmly bound to protein, presumably in covalent linkage. Hydroxyapatite-chromatographic analysis of ADP-ribose residues released from protein by alkaline digestion showed a spectrum of molecular sizes including mono-, oligo- and poly-(ADP-ribose), when chromatin was incubated initially with [14C]NAD+ for 10 min and then for a further 30 min after addition of excess non-radioactive NAD+, only about 10% of the radioactive mono-(ADP-ribose) could be 'chased' into longer-chain molecules. Hydroxyapatite analysis was also used to show that, whereas all ADP-ribose residues were released from protein with NaOH, only 50% of them were susceptible to hydroxylamine. These hydroxylamine-sensitive residues included all size classes, although mono-(ADP-ribose) predominated. Finally, there was an approximately equal distribution of ADP-ribose incorporated into HCl-soluble proteins (including the histones) and HCl-insoluble proteins (including the non-histone proteins) when chromatin was incubated with NAD+ up to 0.5 mM, but at higher NAD+ concentrations more ADP-ribose was incorporated into the HCl-soluble fraction (82% at 4.0 mM-NAD+).

ADP Ribose Transferases↗
PubMed1991

DNA strand breaks and DNA repair response in lymphocytes after chronic in vivo exposure to very low doses of ionizing radiation in mice.

In contrast to the well-documented negative effects of high-dose oxidant exposure, accumulating evidence supports a positive, perhaps essential physiologic role for very low-level oxidant stress. For example, low-level oxidant exposure, within or below the physiologic range, has been reported to stimulate membrane signal transduction, proliferation, antioxidant defense and DNA repair. In the present study, we have examined whether whole-body exposure to low-dose radiation (LDR) results in an alteration in constitutive (steady state) levels of DNA-strand breaks and whether an adaptive increase in DNA-repair response is induced. C57B1/6J mice were exposed to 0.04 Gy (4 cGy) of gamma-radiation as a model of low level oxidant stress. End points measured after chronic in vivo LDR included: (1) constitutive expression of DNA-strand breaks in quiescent spleen cells; (2) sensitivity to DNA damage after high-dose radiation exposure in vitro; (3) repair of constitutive and radiation-induced DNA strand breaks after mitogen stimulation: (4) activity of the DNA-repair associated enzyme, poly(ADP-ribose)transferase (ADPRT) and its substrate, NAD. The results indicated that the constitutive expression of DNA-strand breaks is significantly decreased after chronic LDR; however, DNA-repair capacity after high-dose radiation exposure is not increased above that observed in sham-irradiated mice. Associated with the reduction in constitutive DNA-strand break accumulation was a decrease in resting levels of the DNA-repair-associated enzyme poly(ADP-ribose) transferase (ADPRT). These results are consistent with the interpretation that cumulative DNA damage and associated DNA-repair activity in unstimulated cells are both reduced after chronic LDR exposure.

Adenine Phosphoribosyltransferase↗