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At least 19 recordsLinked to original sources
PubMed1985

Nonenzymic adenosine 5'-diphosphate ribosylation of poly(adenosine diphosphate ribose).

Poly(adenosine 5'-diphosphate ribose) [poly(ADP-ribose]) is spontaneously ADP-ribosylated when it is incubated with nicotinamide adenine dinucleotide, especially in 0.5 M NaCl and at an alkaline pH. The ADP-ribose residues are monomeric and are attached to the middle of polymer chains. The linkage is similar to, and may be identical with, that of the branch points that are created in cells. RNA is also spontaneously ADP-ribosylated, but not DNA.

Animals↗
PubMed1976

Changes in poly(adenosine diphosphate-ribose) and poly(adenosine diphosphate-ribose) polymerase in synchronous HeLa cells.

An antibody has been prepared which is highly specific for poly(adenosine diphosphate-ribose). Neither poly(A), DNA, nor a variety of adenine-containing nucleosides or nucleotides were effective in competing with poly(ADP-ribose) for binding to the antibody. Of all compounds tested, only adenosine diphosphate-ribose competed for binding to the antibody. Unlabeled poly(adenosine diphosphate-ribose) was about 10 000 times more effective in competing with labeled polymer for antibody binding than was adenosine diphosphate-ribose. Using the antibody, the amount of poly(adenosine diphosphate-ribose) was found to increase from early S phase to a peak at mid S with a second, even larger increase seen at the S-G2 transition point in synchronously dividing HeLa cells. Pulse labeling of the polymer with [2-3H]adenosine was also maximal at the same time points. Changes in the levels of poly(adenosine diphosphate-ribose) polymerase activity measured in isolated nuclei coincided with the changes in amounts of polymer present in intact cells during progression from S phase into G2.

Adenine Nucleotides↗
PubMed1979

Nitrosourea interaction with chromatin and effect on poly(adenosine diphosphate ribose) polymerase activity.

Poly(adenosine diphosphate ribose) polymerase, a chromatin-bound enzyme, was stimulated 150 to 200% after treatment of HeLa cells with methylnitrosourea (MNU). In contrast, a slight inhibitory effect on enzyme activity was observed after treatment of cells with various concentrations of chloroethylnitrosoureas. To define precisely the differential effects of nitrosoureas on the enzyme activity, their interactions with chromatin substructure were studied. A nonrandom, in vivo alkylation of chromatin DNA by equimolar concentrations of MNU and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was revealed by digestion of nuclei from drug-treated cells with micrococcal nuclease and DNase I. [methyl-14C]MNU interacted preferentially with the more accessible regions of chromatin, the internucleosome linkers, whereas, the [chloroethyl-14C]CCNU alkylated the nucleosomal core DNA to a greater extent. These two drugs also differed in their extent of covalent modification of histone and nonhistone chromosomal protein. The binding of MNU to histones was greater than of CCNU. CCNU mainly affected nonhistone proteins. This difference in the reactivity of methyl and chloroethyl nitrosoureas with chromatin may relate to their differential effect on poly(adenosine diphosphate ribose) polymerase activity, as well as to their carcinogenic and antitumor properties.

Alkylation↗
PubMed1977

Natural occurence of a biopolymer, poly (adenosine diphosphate ribose).

Evidence for the natural occurrence of poly(adenosine diphosphate ribose) in vivo was obtained using a sensitive radioimmunoassay and poly(adenosine diphosphate ribose) glycohydrolase, which specifically hydrolyzes poly(adenosine diphosphate ribose). Calf thymus, liver, kidney, brain, pancreas and spleen contained poly(adenosine diphosphate ribose). Naturally occurring poly(adenosine diphosphate ribose) in calf thymus is composed of molecules of various chain lengths, like that synthesized by an in vitro system. Calf thymus was estimated to contain about 0.02 microgram/mg DNA of poly(adenosine diphosphate ribose).

Animals↗
PubMed1984

Monoclonal antibodies to poly(adenosine diphosphate ribose) recognize different structures.

Two hybridomas producing monoclonal antibodies to poly(adenosine diphosphate ribose) [poly(ADP-Rib)] were established. One antibody, 10H (IgG3, kappa), bound to most of the poly(ADP-Rib) preparation, which consisted of molecules of various sizes of more than 20 ADP-Rib residues. The binding of this antibody was inhibited by not only poly-(ADP-Rib) but also a monomer unit of poly(ADP-Rib), Ado(P)-Rib-P. The sites protected by antibody 10H were isolated and analyzed by hydrolysis with alkaline phosphomonoesterase and then snake venom phosphodiesterase. The sites contained the same amounts of monomer units and branched portions [Ado(P)-Rib(P)-Rib-P] as the original poly(ADP-Rib) molecules but a lower average number of branched portions per molecule than in the original molecules. The other antibody, 16B (IgM, lambda), reacted with only 50% of the radioactive poly(ADP-Rib), and its binding was not inhibited by a monomer unit. This antibody protected 25% of all the poly(ADP-Rib) molecules from hydrolysis by snake venom phosphodiesterase. The protected sites contained twice as many branched portions per molecule as the original poly(ADP-Rib) molecules. These results show that the two monoclonal antibodies recognize different structures of poly-(ADP-Rib); 10H antibody recognizes the linear structure with ribose-ribose linkages, and 16B antibody may recognize specific structures, including the branched portions of poly-(ADP-Rib).

Animals↗
PubMed1979

Structure of poly(adenosine diphosphate ribose): identification of 2'-[1''-ribosyl-2''-(or 3''-)(1'''-ribosyl)]adenosine-5',5'',5'''-tris(phosphate) as a branch linkage.

Poly([14C]adenosine diphosphate ribose) was synthesized from [14C]NAD+ with calf thymus nuclei. The fraction containing poly(adenosine diphosphate ribose) eluted with 0.22--0.40 M phosphate buffer (pH 6.8) from a hydroxylapatite column, was completely hydrolyzed with venom phosphodiesterase, and was separated by DEAE-Sephadex A-25 column chromatography in 7 M urea. A new compound, which constituted 2% of the products from poly(adenosine diphosphate ribose), was found in addition to the expected products--i.e., 5'-AMP, 2'-(1''-ribosyl)adenosine-5',5''-bis(phosphate), and its derivatives. This compound was identified as 2'-[1''-ribosyl 2''-(or 3''-)(1'''-ribosyl)]adenosine-5',5'',5'''-tris(phosphate). The existence of this compound is evidence of a branching structure of poly(adenosine diphosphate ribose), which was previously thought to be a linear molecule. The content of this compound suggests that the frequency of branching is about 1 per 20--30 adenosine diphosphate ribose residues of high molecular weight poly(adenosine diphosphate ribose).

Chemical Phenomena↗
PubMed1982

Purification and characterization of human lymphoid poly(adenosine diphosphate ribose) polymerase.

Poly(ADP-ribose) polymerase has been purified 12 000-fold from human tonsils with an 83% recovery of enzymatic activity relative to that of the initial homogenate. The specific activity of the purified enzyme is 862 units/mg of protein. The isolated protein has a molecular weight of approximately 116 000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The apparent Km for NAD+ is estimated to be 185 microM at pH 8.0 and 37 degrees C. The purified enzyme has an absolute requirement for exogenous DNA for catalytic activity, and the reaction is enhanced by the addition of purified histone H1. The enzyme does not require magnesium or other divalent cations for activity. Enzyme activity is inhibited by p-(hydroxymercuri)benzoate and N-ethylmaleimide. Thymidine, theophylline, nicotinamide, and 5-methylnicotinamide markedly inhibit enzyme activity whereas ADP-ribose, 3',5'-cAMP, and sodium fluoride have a minimal effect on enzyme activity. Autoradiograms of labeled products of the reaction catalyzed by the purified enzyme at different concentrations of NAD+ and at different incubation times show that at low concentrations of NAD+ and after short incubations, poly(ADP-ribosyl)ation of the enzyme occurs preferentially over that of histone H1; at higher concentrations of NAD+ or after longer incubations, poly(ADP-ribosyl)ation of histone H1 is increased.

Cations, Divalent↗
PubMed1977

Purification and properties of poly(adenosine diphosphate ribose) synthetase.

Poly(ADP-ribose) synthetase has been purified approximately 5000-fold from rat liver nuclei. The activity of the purified enzyme is absolutely dependent upon the presence of native or synthetic DNA, and the further addition of histone(s) stimulates the activity 3- to 5-fold. When the ADP-ribosylated material synthesized in the absence or presence of various histones is analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the major product in all cases migrates between histones H1 and H3-H2B with the same RF value of 0.58 relative to the marker dye. No ADP-ribose was found to co-electrophorese with any of thehistones. The addition of histones does not affect the chain number of the poly(ADP-ribose) synthesized but does result in an increase in the average chain length of the polymer. In the presence of histones, the Km for NAD+ decreases from 80 micron to 25 micron and the Vmax doubles. These results indicate that, in the purified poly(ADP-ribose) synthetase system, histones are not ADP-robosylated but act as allosteric activators.

Animals↗
PubMed1978

Demonstration of high molecular weight poly (adenosine diphosphate ribose).

An electrophoretic system was established that resolves poly(adenosine diphosphate ribose), enzymatically synthesized polymer from NAD+, by size difference of one residue on polyacrylamide gel. The existence of a polymer of at least 65 residues was demonstrated by band counting in this system. The polymer showed a heterogeneous size distribution on the electrophoregram, and the molecular weight of the largest polymer was deduced to be more than 4.5 X 10(5) daltons. The discrepancy between the size, estimated by electrophoresis, and the chain length, determined by the ratio of total radioactivity to that derived from the terminus, suggests that the polymer has a branched structure.

Animals↗
PubMed1978

Formation and characterization of antibody against 2'-(5"-phosphoribosyl)-5' AMP, the monomer form of poly(adenosine diphosphate ribose).

Specific antibody against 2'-(5"-phosphoribosyl)-5'AMP (PR-AMP), a monomer of poly(adenosine diphosphate ribose) (poly(ADP-Rib)), was produced by immunizing a rabbit with PR-AMP coupled to bovine serum albumin (BSA). Antibody against PR-AMP was purified 53-fold from serum by (NH4) 2SO4 precipitation, and BSA-Sepharose 4B, DEAE-cellulose and (PR-AMP)-BSA-Sepharose 4B column chromatographies. Inhibition experiments show that the adenine ring, 5'-phosphate residue and ribose-ribose bond of PR-AMP were essential for the antigenic determinant of PR-AMP. Anti PR-AMP antibody bound, not only with PR-AMP, but also with poly(ADP-Rib) of various chain lengths, while anti poly(ADP-Rib) antibody bound with poly(ADP-Rib) but not with PR-AMP.

Adenosine Monophosphate↗
PubMed1978

Bovine thymus poly(adenosine diphosphate ribose) polymerase.

About 1,300-fold purification of poly(adenosine diphosphate ribose) polymerase has been achieved from the extract of bovine thymus with a recovery of 10 to 20%. The final preparation has a purity of 99%, and the enzyme is composed of a single peptide with a molecular weight of 130,000. The purified enzyme required NAD+, Mg2+, a thiol compound, DNA, and histones for full activity. Whereas DNA is essential for activation of the enzyme, histones are not. The observed stimulation of the reaction by histones is shown to be due to masking of the inhibitory effect of contaminating denartured DNA in native DNA preparation. The concentration of DNA required for half-maximal enzyme activity (apparent Km for DNA) is proportional to the concentration of enzyme in the reaction mixture. The minimum estimation of the number of nucleotide pairs of DNA required for half-maximal activation of one enzyme molecule is 220 to 240 for bulk of calf thymus DNA, while the value is 10 for a calf thymus DNA fraction, "active DNA," which was separated from the enzyme fraction in a stage of the purification. These results suggest that the enzyme is activated by binding to a specific site on calf thymus DNA. The apparent Km for NAD+ and the maximum velocity of the enzyme are estimated to be 60 micrometer and 0.91 mumolper min per mg, respectively.

Animals↗
PubMed1985

Induction of rat pancreatic B-cell tumors by the combined administration of streptozotocin or alloxan and poly(adenosine diphosphate ribose) synthetase inhibitors.

Streptozotocin and alloxan were administered to Wistar rats in combination with poly(adenosine diphosphate ribose) synthetase inhibitors. Ten to 16 months after the injection of streptozotocin (50 mg/kg body weight i.v.) and 3-aminobenzamide (345 mg/kg i.v.), streptozotocin (50 mg/kg) and nicotinamide (350 mg/kg i.p.), streptozotocin (50 mg/kg) and picolinamide (250 mg/kg i.p.), alloxan (40 mg/kg i.v.) and nicotinamide (350 mg/kg), alloxan (40 mg/kg) and 3-aminobenzamide (345 mg/kg), and alloxan (40 mg/kg) and picolinamide (250 mg/kg), pancreatic islet cell tumors developed in 100, 98, 60, 26, 22, and 20% of surviving rats, respectively. However, after the single injection of streptozotocin and alloxan, islet cell tumors developed in 42 and 11% of surviving rats, respectively. The tumors were rich in B-granules on electron micrographs and contained as large amounts of proinsulin messenger RNA as normal pancreatic islets. The results indicate that poly(adenosine diphosphate ribose) synthetase inhibitors enhance the tumorigenic effect of streptozotocin and alloxan on islet B-cells.

Adenoma, Islet Cell↗
PubMed1978

Synthesis of DNA and poly(adenosine diphosphate ribose) in normal and chronic lymphocytic leukemia lymphocytes.

Peripheral blood lymphocytes were isolated from 9 patients with chronic lymphocytic leukemia (CLL) and 12 normal control donors. The cells were assayed for synthesis of DNA and poly-(adenosine diphosphate ribose) (poly[ADPR]) immediately after isolation and on successive days following their treatment with phytohemagglutinin (PHA). Two different techniques were used to measure DNA synthesis. In the standard technique, DNA synthesis was measured by incubating intact cells with [(3)H]deoxythymidine. In the new technique, the lymphocytes were first rendered permeable to nucleotides, then DNA synthesis was measured by incubating them with [(3)H]deoxythymidine triphosphate in the presence of deoxyATP, deoxyGTP, deoxyCTP, ATP, and Mg(++). Both assays showed the anticipated rise in DNA synthesis after PHA stimulation of normal cells. PHA-stimulated lymphocytes from patients with CLL demonstrated low levels of DNA synthesis in both assay systems. The initial levels of poly(ADPR) synthesis were greater in CLL lymphocytes than in normal cells. Studies with a T-cell-depleted population of normal cells showed the same activity for poly(ADPR) synthesis that was demonstrated by the original population of normal cells. PHA stimulation produced an increase in poly(ADPR) synthesis in both the normal and CLL cells. The increase in poly(ADPR) synthesis in normal cells was coincident with the increase in DNA synthesis. The increase in poly(ADPR) synthesis in the CLL cells was dissociated from the delayed and diminished increase in DNA synthesis. Thus, CLL cells have higher than normal initial levels of poly(ADPR) synthesis. Poly(ADPR) synthesis is dissociated from DNA synthesis in CLL cells whereas it varies directly with DNA synthesis in normal lymphocytes.

Cells, Cultured↗