Poly(adenosinediphosphoribose) polymerase inhibitors stimulate unscheduled DNA synthesis in normal human lymphocytes

Sims, James L.; Sikorski, Georgina W.; Catino, Donna M.; Berger, Sosamma J.; Berger, Nathan A.

doi:10.1021/bi00537a017

Cited by 166 publications

(58 citation statements)

References 20 publications

(28 reference statements)

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“…These findings raise the question of whether alkylation damage induces primarily mono-and oligo(ADP-ribosy1)ation in the living cell with still undiscovered effects on chromatin metabolism, or whether longer polymers are originally formed which are subject to rapid degradation by poly(ADP-ribose) glychohydrolase. The latter possibility is consistent with previous reports documenting a very high turnover rate and short half-life of protein-bound poly(ADP-ribose) formed under comparable conditions [60,131. It therefore appears conceivable that the isolated poly(ADP-ribose) -protein conjugates consist of glycohydrolase-resistant remnants accumulating during the dimethyl sulfate treatment.…”

Section: Discussionsupporting

confidence: 93%

“…Seven major components could be discerned on dodecyl sulfate gels (molecular mass 43,60,66, 86, 100, 110 and 170 kDa) while control cells indicated only slight staining at above 200 kDa. The most abundant conjugate formed in response to alkylation damage was further purified using preparative gel electrophoresis and identified on the basis of its intrinsic enzymic activity as automodified poly(APD-ribose) synthase.…”

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confidence: 94%

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Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Adamietz

1987

Eur J Biochem

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The endogenous poly(ADP-ribosyl) -nonhistone protein conjugates were isolated from dimethyl-sulfatetreated rat hepatoma AH 7974 cells using aminophenylboronic-acid -agarose chromatography. Seven major components could be discerned on dodecyl sulfate gels (molecular mass 43,60,66, 86, 100, 110 and 170 kDa) while control cells indicated only slight staining at above 200 kDa. The most abundant conjugate formed in response to alkylation damage was further purified using preparative gel electrophoresis and identified on the basis of its intrinsic enzymic activity as automodified poly(APD-ribose) synthase. In addition, topoisomerase I activity was found associated with a 60-kDa peptide. ADP-ribosylated endonucleases and actin were not detectable. The purified conjugate fraction contained maximally 8.8 nmol/mg ADP-ribose and 7.9 nmol/mg oligo(ADPribose) with a mean chain length of 2.3 residues. The modifying (ADP-ribosyl), groups were attached to its acceptors by a hydroxylamine-insensitive bond and had practically no effect on the DNA affinity of either poly(ADP-ribose) synthase or topoisomerase I.Fragmentation of cellular DNA as induced by chemical or physical stress enhances the endogenous synthesis of poly(ADP-ribose) in the eucaryotic cell (for reviews see [l-31). The poly(ADP-ribose) synthase responsible for this reaction is capable of transferring the ADP-ribose moiety from the substrate NAD to a variety of chromosomal acceptor proteins with subsequent elongation to linear and branched homopolymers [4]. Formation of these products has been related to the regulation of several chromatin functions, especially those including intermediate nicking and resealing of DNA strands [5], such as cellular differentiation [6-91 and the DNA repair reactions [lo -131. The activity of the purified synthase was found to be completely dependent on binding to broken DNA [14] and inhibitors of the enzyme proved to be co-cytostatic [ l l , 15, 161 and co-carcinogenic [17-201 with DNA-damaging agents. These biological effects are apparently restricted to dividing cells, suggesting that poly(ADPribose) metabolism is required for the recovery of damaged cells progressing through the cell cycle but not for reactions directly involved in DNA excision repair [21,22]. Accordingly, inhibitors of poly(ADP-ribose) synthesis did not affect the rate of DNA ligation in alkylated HeLa cells [23,24] or mouse embryo fibroblasts [21], whereas strand-break frequency was enhanced and some breaks appeared to remain unrepaired in the absence of poly(ADP-ribose) synthesis. The molecular mechanism by which poly(ADP-ribose) can prevent alkylation-induced cell death ist still not understood. A frequent explanation is that poly(ADP-ribose) may regulate cellular events by directy modulating the enzymic activities of the modified proteins [5] in analogy to the action of extranuclear mono(ADP-ribosyl) transferases [3]. This view relies on the observation that poly(ADP-ribosy1)ation inhibits the activities of many nuclear enzymes in vitro: Ca2+/Mg2-dependent ...

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 94%

Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Adamietz

1987

Eur J Biochem

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“…To inhibit poly(ADP-ribosyl) polymerase, we used 3-ABA at low concentrations (1, 2.5 mM) reported to have minimal effects on cell metabolism (43) and to inhibit the enzyme specifically (44) and which did not alter fiber uptake. 3-ABA, but not a closely related structural analogue 3-ABOA, significantly reduced apoptosis due to asbestos (29). The reduction of apoptosis by inhibition of this enzyme supports a role for asbestos-induced DNA damage in mediating apoptosis.…”

Section: Discussionmentioning

confidence: 73%

Crocidolite Asbestos Induces Apoptosis of Pleural Mesothelial Cells: Role of Reactive Oxygen Species and Poly(ADP-Ribosyl) Polymerase

Broaddus¹,

Yang²,

Scavo³

et al. 1997

Environmental Health Perspectives

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Mesothelial cells, the progenitor cells of the asbestos-induced tumor mesothelioma, are particularly sensitive to the toxic effects of asbestos, although the molecular mechanisms by which asbestos induces injury in mesothelial cells are not known. We asked whether asbestos induced apoptosis in mesothelial cells and whether reactive oxygen species were important. Rabbit pleural mesothelial cells were exposed to crocidolite asbestos or control particles (1-10 pg/cm2) over 24 hr and evaluated for oligonucleosomal DNA fragmentation, loss of membrane phospholipid asymmetry, and nuclear condensation. Asbestos fibers, not control particles, induced apoptosis in mesothelial cells by all assays. Induction of apoptosis was dose dependent; crocidolite (5 pg/cm2) induced apoptosis 115.0 ± 1.1 %, mean ± SE; n = 12) versus control particles (<4%), as measured by appearance of nuclear condensation. Apoptosis induced by asbestos, but not by actinomycin D, was inhibited by extracellular catalase, superoxide dismutase in the presence of catalase, hypoxia (8% oxygen), deferoxamine, and 3-aminobenzamide (an inhibitor of the nuclear enzyme, poly(adenosine diphosphate-ribosyl) polymerase). We conclude that asbestos induces apoptosis in mesothelial cells via reactive oxygen species. We speculate that escape from this pathway could allow the abnormal survival of mesothelial cells with asbestosinduced mutations.

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“…To inhibit poly(ADP-ribosyl) polymerase, we used 3-ABA at low concentrations (1, 2.5 mM) reported to have minimal effects on cell metabolism (44) and to inhibit the enzyme specifically (45), and which did not alter fiber uptake. The 3-ABA, but not a closely related structural analogue 3-ABOA, significantly reduced the apoptosis due to asbestos (30). The reduction of apoptosis by inhibition of this enzyme supports a role for asbestos-induced DNA damage in mediating apoptosis.…”

Section: Discussionmentioning

confidence: 76%

Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species.

Broaddus¹,

Yang²,

Scavo³

et al. 1996

J. Clin. Invest.

155

102

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Mesothelial cells, the progenitor cell of the asbestos-induced tumor mesothelioma, are particularly sensitive to the toxic effects of asbestos, although the molecular mechanisms by which asbestos induces injury in mesothelial cells are not known. We asked whether asbestos induced apoptosis in mesothelial cells and whether reactive oxygen species were important. Pleural mesothelial cells (rabbit or human) were exposed to asbestos (crocidolite, amosite, or chrysotile) or control particles at moderate doses (1-10 g/cm 2 ) over 24 h and evaluated for oligonucleosomal DNA fragmentation, loss of membrane phospholipid asymmetry, and nuclear condensation.

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Poly(adenosinediphosphoribose) polymerase inhibitors stimulate unscheduled DNA synthesis in normal human lymphocytes

Cited by 166 publications

References 20 publications

Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Crocidolite Asbestos Induces Apoptosis of Pleural Mesothelial Cells: Role of Reactive Oxygen Species and Poly(ADP-Ribosyl) Polymerase

Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species.

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