Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelium-associated enzyme xanthine oxidase is known to generate reactive oxygen intermediates which may damage the surrounding tissue. We investigated whether reactive oxygen intermediates released by xanthine oxidase exert a toxic effect on isolated rat islet cells. The xanthine oxidase (25 mU/ml)/hypoxanthine (0.5 mmol/l) system released reactive oxygen intermediates in vitro as detected by luminol in a chemiluminescence analysing system. The addition of nicotinamide inhibited the release of reactive oxygen intermediates in a dose-dependent manner (50% inhibition at 20 mmol/l). Exposure of islet cells to enzyme generated reactive oxygen intermediates caused lysis of 39% of the cells within 15 h. Monitoring the mitochondrial function of islet cells by the conversion of tetrazolium bromide to its formazan product revealed a significant reduction of the respiratory activity down to 51% of that of the controls by 30 min after the initiation of the xanthine oxidase reaction. Mitochondrial dysfunction preceded plasma membrane damage. The addition of nicotinamide, a radical scavenger and inhibitor of the DNA repair enzyme poly(ADP-ribose) synthetase protected the islet cells from lysis and partially preserved their mitochondrial activity in the presence of reactive oxygen intermediates. We conclude that activation of the endothelial enzyme xanthine oxidase, known to be induced by mediators of immune cells or by episodes of ischaemia and reperfusion causes islet cell damage with subsequent cell death in early phases of pancreatic islet cell destruction.
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PMID:Oxygen radicals generated by the enzyme xanthine oxidase lyse rat pancreatic islet cells in vitro. 147 12

The appearance of DNA replication intermediates was investigated in a human fibroblast strain (46 BR) which is hypersensitive to the lethal effects of 3-aminobenzamide. 3-Aminobenzamide is an inhibitor of poly(ADP-ribose) synthetase and modulates DNA ligase activity. We detected the same intermediates (10 kb DNA and Okazaki-fragments) as in normal fibroblasts, but kinetics and amounts of intermediates were altered, either as a result of, or in order to overcome the defect in the cells.
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PMID:Altered formation of DNA replication intermediates in human 46 BR fibroblast cells hypersensitive to 3-aminobenzamide. 249 1

To elucidate the molecular mechanism by which poly(ADP-ribose) participates in DNA excision repair, we examined the effect of poly(ADP-ribose) on DNA ligase activity in DNA/histone and reconstituted chromatin systems. The ligase activity was markedly inhibited by histones; the inhibition varied depending on histone subfraction and DNA/histone ratio. Poly(ADP-ribose), either exogenous or synthesized in situ by poly(ADP-ribose) synthetase, reversed this inhibition by histone almost completely. This effect was specific for poly(ADP-ribose); polyanions such as mRNA, rRNAs, tRNA, and synthetic poly(A) were less effective or ineffective. The ligase activity with reconstituted chromatin as the substrate was about half of that with free DNA whereas the activities with these two substrates were almost the same in the presence of poly(ADP-ribose) synthesized in situ. The polymers synthesized under these conditions were exclusively bound to the synthetase. Together with our previous finding that the enzyme is the main acceptor of the polymer in DNA-damaged cells, these results suggest that poly(ADP-ribose) in the synthetase-bound form counteracts inhibition by histones and activates DNA ligase to rejoin DNA strands in polynucleosomal structures.
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PMID:Activation of DNA ligase by poly(ADP-ribose) in chromatin. 640 17

The molecular mechanism by which poly(ADP-ribose) participates in DNA repair was investigated using purified DNA ligase in DNA-histone systems. The ligase activity was markedly inhibited by histones; the inhibition was greater than 80% with histone H1 at concentrations equal to DNA. This inhibition was reversed efficiently by poly(ADP-ribose), either added exogenously or synthesized in situ with poly(ADP-ribose) synthetase. The reversal effect was specific for poly(ADP-ribose); other polyanions such as mRNA, rRNA's, tRNA, and synthetic poly(A) were less effective or totally ineffective. The poly(ADP-ribose) effect appeared to be caused by binding to histones and decreasing DNA-histone interactions. Poly(ADP-ribose) also had high affinity for DNA ligase. These observations, together with the findings of absolute dependence of poly(ADP-ribose) synthetase activity on DNA strand ends and extensive automodification of the synthetase in DNA-damaged cells, suggested a possible mechanism of poly(ADP-ribose) action in DNA repair, in which auto-modified poly(ADP-ribose) synthetase serves as a link between DNA damage and activation of DNA ligase.
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PMID:Inhibition of DNA ligase activity by histones and its reversal by poly(ADP-ribose). 665 29