Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dimethylnitrosamine maximally inhibits rat liver nuclear RNA synthesis by 50% at a dose of 40 mg/kg of body weight. The inhibition develops during the first 4 hr and persists through the 12th hr. All parenchymal cells of the lever lobule seem to be affected. The decreased RNA synthesis can be accounted for entirely by an inhibition of the RNA polymerase activities quantitatively solubilized and partially purified. A similar inhibition of the polymerase activities was demonstrated in the intact nuclei by inactivating the endogenous template with actinomycin D and assaying the polymerases with an added exogenous template, poly(deoxy-adenylate-deoxythymidylate). Chromatin was prepared by two methods differing in the extent to which they remove the endogenous polymerase activity. Each preparation was transcribed with either added Escherichia coli or partially purified rat liver nucleoplasmic RNA polymerase. With either polymerase or chromatin preparation, no inhibition of the template activity of liver nuclear chromatin isolated from the DMN-treated animals was detected. A similar mechanism of inhibition of RNA synthesis was produced by the action of the methylating agent methyl methanesulfonate on whole nuclei in vitro. The dose-dependent inhibition of RNA synthesis could be accounted for by an inhibition of the RNA polymerase activities quantitatively solubilized and partially purified from the affected nuclei. Chromatin prepared from the methyl methanesulfonate-treated nuclei had a normal template capacity with either E. coli or rat liver nucleoplasmic RNA polymerase. No preferential methylation of the RNA polymerases by [14C]methyl methanesulfonate could be demonstrated. It is concluded that the action of the two methylating agents on RNA metabolism is similar and that the inhibition of liver nuclear RNA synthesis results from inactivation of the RNA polymerases. At the same time, dimethylnitrosamine and methyl methanesulfonate leave the chromatin template intact, at least quantitatively, for the synthesis of RNA. The implications of such an effect on RNA synthesis are discussed.
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PMID:Inhibition of rat liver RNA polymerases by action of the methylating agents dimethylnitrosamine in vivo and methyl methanesulfonate in vitro. 17 32

Dimethylnitrosamine (DMNA) strongly inhibited RNA synthesis in mouse liver under conditions when the nucleotide pattern, rate of nucleotide synthesis and phosphorylation ratio were unaffected. (An unidentified, probably non-nucleotide, component in the acid-soluble liver fraction was selectively reduced.) The inhibition of RNA synthesis was associated with a decrease in the RNA polymerase activity of isolated liver nuclei, well established already 45 min after DMNA administration. The reduced activity included both Mg2+- and Mn2+/(NH4)2SO4-stimulated polymerase functions. The inhibition in vivo involved the whole complement of RNA, including poly (A)-containing RNA and isolated poly(A) sequences. The transfer of labelled RNA from the nucleus to the cytoplasm was not impaired. There was no detachment of poly(A)-containing RNA from the microsomes, and the proportion of tightly membrane-bound microsomal RNA and poly(A) sequences was not reduced as determined by use of a flotation technique. No breakage or shortening of the poly(A) chains was indicated by sedimentation analysis.
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PMID:RNA metabolism and poly(A) distribution in mouse liver following administration of dimethylnitrosamine. 66 22

1. Administration of a single dose of dimethylnitrosamine to rats temporarily fed on a protein-deficient diet causes a high incidence of kidney tumours. The effect of such a dose of dimethylnitrosamine (40mg/kg body wt.) on metabolism of nucleic acids and protein in rat liver and kidneys was examined during the week immediately after administration. 2. Incorporation of [(14)C]leucine and [(14)C]orotate into hepatic macromolecules was inhibited within 5h of injection of dimethylnitrosamine, and did not recover for at least 5 days. Interpretation of these results is complicated by the concomitant extensive hepatic necrosis. 3. Renal RNA synthesis was assayed by incorporation of [(14)C]orotate in vivo and measurement of DNA-dependent RNA polymerase activity in vitro. Both systems indicate biphasic inhibition; minimal activity was recorded 9h and 3 days after treatment. Changes in incorporation of [(14)C]leucine into renal protein were similar but less marked. 4. Sucrose-density-gradient analysis of renal cytoplasmic RNA indicated increased synthesis of rRNA 24h after injection of the nitrosamine. The rate of loss of radioactivity from kidney ribosomes pre-labelled with [(14)C]orotate was not modified by dimethylnitrosamine. 5. Dimethylnitrosamine increased incorporation of [(3)H]-thymidine into renal DNA. The three distinct periods of stimulated synthesis observed are discussed, with particular reference to recently published morphological studies of the sequential development of kidney tumours induced by dimethylnitrosamine in protein-depleted rats.
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PMID:Effect of a single dose of dimethylnitrosamine on biosynthesis of nucleic acid and protein in rat liver and kidney. 514 59

Following i.p. injection of dimethylnitrosamine into male C57BL mice, synthesis of liver nuclear heterogeneous RNA was inhibited significantly, reaching approximately 20% of control within 2 hr of a dose of 40 mg/kg. Synthesis of nucleolar RNA was also inhibited, although to a smaller extent, reaching about 70% of control after the same treatment. These effects were observed both during RNA synthesis in vivo and during in vitro transcription with isolated nuclei and nucleoli. Examination of RNA polymerases I and II, isolated and partially purified by diethylaminoethyl Sephadex column chromatography, did not indicate any change either in their activities in the transcription of exogenous DNA or in their in vivo binding to chromatin. On the other hand, the activity of purified chromatin as a template for transcription by added, partially purified RNA polymerase II was significantly reduced, suggesting that carcinogen-induced damage to chromatin was the cause of the observed inhibition of heterogeneous RNA synthesis. When purified DNA was used in place of chromatin as a template for transcription by partially purified RNA polymerase II, no inhibition was observed. Dimethylnitrosamine treatment had a pronounced effect on the kinetics of appearance of the cytoplasmic RNA species. Four hr after a 40-mg/kg dose of dimethylnitrosamine, the rate of appearance in the cytoplasm of polyadenylate-containing RNA was inhibited by 50%, while that of 4S, 18S, and 28S ribosomal RNA was inhibited by over 80%.
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PMID:Effects of dimethylnitrosamine on RNA synthesis and metabolism in mouse liver. 620 12