Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We examined the role of transcription in directing repair of DNA damage in active genes by comparing the repair of thymine glycols produced by H2O2 and of UV-induced pyrimidine dimers on each strand of the GAL7 gene of Saccharomyces cerevisiae. Repair of both thymine glycols and pyrimidine dimers on the transcribed strand of the gene occurs two to three times faster than on its nontranscribed strand or in the genome overall. When the gene is inactive, no preferential or strand-selective repair is observed. Using a yeast strain containing a temperature-sensitive mutation in one of the subunits of RNA polymerase II, we find that inactivating RNA polymerase II by shifting the cells to the nonpermissive temperature during repair eliminates the strand selectivity of repair under conditions where repair on the nontranscribed strand of the gene and in the genome overall are only slightly affected. Our observation of strand-selective repair of thymine glycols in the GAL7 gene is the first evidence that this repair process occurs for a nonbulky lesion. In addition, we demonstrate that the transcriptional complex plays a critical role in directing repair to the transcribed strand of active genes.
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PMID:Strand-selective repair of DNA damage in the yeast GAL7 gene requires RNA polymerase II. 142 64

During carbon-starvation-induced entry into stationary phase, Escherichia coli cells exhibit a variety of physiological and morphological changes that ensure survival during periods of prolonged starvation. Induction of 30-50 proteins of mostly unknown function has been shown under these conditions. In an attempt to identify C-starvation-regulated genes we isolated and characterized chromosomal C-starvation-induced csi::lacZ fusions using the lambda placMu system. One operon fusion (csi2::lacZ) has been studied in detail. csi2::lacZ was induced during transition from exponential to stationary phase and was negatively regulated by cAMP. It was mapped at 59 min on the E. coli chromosome and conferred a pleiotropic phenotype. As demonstrated by two-dimensional gel electrophoresis, cells carrying csi2::lacZ did not synthesize at least 16 proteins present in an isogenic csi2+ strain. Cells containing csi2::lacZ or csi2::Tn10 did not produce glycogen, did not develop thermotolerance and H2O2 resistance, and did not induce a stationary-phase-specific acidic phosphatase (AppA) as well as another csi fusion (csi5::lacZ). Moreover, they died off much more rapidly than wild-type cells during prolonged starvation. We conclude that csi2::lacZ defines a regulatory gene of central importanc e for stationary phase E. coli cells. These results and the cloning of the wild-type gene corresponding to csi2 demonstrated that the csi2 locus is allelic with the previously identified regulatory genes katF and appR. The katF sequence indicated that its gene product is a novel sigma factor supposed to regulate expression of catalase HPII and exonuclease III (Mulvey and Loewen, 1989). We suggest that this novel sigma subunit of RNA polymerase defined by csi2/katF/appR is a central early regulator of a large starvation/stationary phase regulon in E. coli and propose 'rpoS' ('sigma S') as appropriate designations.
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PMID:Identification of a central regulator of stationary-phase gene expression in Escherichia coli. 184 9

The Escherichia coli mutant (ppk) lacking the enzyme polyphosphate kinase, which makes long chains of inorganic polyphosphate (poly P), is deficient in functions expressed in the stationary phase of growth. After 2 days of growth in a medium limited in carbon sources, only 7% of the mutants survived compared with nearly 100% of the wild type; the loss in viability of the mutant was even more pronounced in a rich medium. The mutant showed a greater sensitivity to heat, to an oxidant (H2O2), to a redox-cycling agent (menadione), and to an osmotic challenge with 2.5 M NaCl. After a week or so in the stationary phase, mutant survivors were far fewer in number and were replaced by an outgrowth of a small-colony-size variant with a stable genotype and with improved viability and resistance to heat and H2O2; neither polyphosphate kinase nor long-chain poly P was restored. Suppression of the ppk feature of heat sensitivity by extra copies of rpoS, the gene encoding the RNA polymerase sigma factor that regulates some 50 stationary-phase genes, further implicates poly P in promoting survival in the stationary phase.
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PMID:Inorganic polyphosphate supports resistance and survival of stationary-phase Escherichia coli. 863 17

Methimazole (MMI) and propylthiouracil (PTU) are common antithyroid drugs for treating hyperthyroidism because the 2 drugs inhibit thyroid peroxidase (TPO)-catalyzed thyroid hormone formation. We studied whether the 2 drugs actually inhibit cellular TPO activity in cultured porcine follicles. Porcine follicles were cultured in the presence of 1 mU/mL thyrotropin (TSH) for 7 days. Then follicles were exposed to MMI or PTU in the presence of 0.1 microM Kl for 2 days. TPO activity was measured in the 100,000 x g-pellet of the thyroid sonicate by the guaiacol oxidation method. Exposure to MMI (1 microM and 10 microM) or PTU (10 microM and 100 microM) for 2 days caused a significant increase in cellular TPO activity; 100 microM MMI inhibited cellular TPO activity. The presence of cyclic adenosine monophosphate (cAMP)-generating system (forskolin) in TSH-free medium increased MMI-mediated TPO activity. Cyclohexamide inhibited MMI-mediated TPO activation, indicating that new protein synthesis is required for increased TPO activity. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed an increase in TPO mRNA by PTU or MMI. In conclusion, MMI and PTU at therapeutic concentrations can increase TPO mRNA and cellular TPO activity, although the 2 drugs inhibit the TPO-H2O2-mediated catalytic reaction.
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PMID:Methimazole and propylthiouracil increase cellular thyroid peroxidase activity and thyroid peroxidase mRNA in cultured porcine thyroid follicles. 1036 84

We have cloned a 3.6-kb genomic DNA fragment from Pseudomonas aeruginosa harboring the rpoA, rplQ, katA, and bfrA genes. These loci are predicted to encode, respectively, (i) the alpha subunit of RNA polymerase; (ii) the L17 ribosomal protein; (iii) the major catalase, KatA; and (iv) one of two iron storage proteins called bacterioferritin A (BfrA; cytochrome b1 or b557). Our goal was to determine the contributions of KatA and BfrA to the resistance of P. aeruginosa to hydrogen peroxide (H2O2). When provided on a multicopy plasmid, the P. aeruginosa katA gene complemented a catalase-deficient strain of Escherichia coli. The katA gene was found to contain two translational start codons encoding a heteromultimer of approximately 160 to 170 kDa and having an apparent Km for H2O2 of 44.7 mM. Isogenic katA and bfrA mutants were hypersusceptible to H2O2, while a katA bfrA double mutant demonstrated the greatest sensitivity. The katA and katA bfrA mutants possessed no detectable catalase activity. Interestingly, a bfrA mutant expressed only approximately 47% the KatA activity of wild-type organisms, despite possessing wild-type katA transcription and translation. Plasmids harboring bfrA genes encoding BfrA altered at critical amino acids essential for ferroxidase activity could not restore wild-type catalase activity in the bfrA mutant. RNase protection assays revealed that katA and bfrA are on different transcripts, the levels of which are increased by both iron and H2O2. Mass spectrometry analysis of whole cells revealed no significant difference in total cellular iron levels in the bfrA, katA, and katA bfrA mutants relative to wild-type bacteria. Our results suggest that P. aeruginosa BfrA may be required as one source of iron for the heme prosthetic group of KatA and thus for protection against H2O2.
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PMID:Bacterioferritin A modulates catalase A (KatA) activity and resistance to hydrogen peroxide in Pseudomonas aeruginosa. 1036 48

Metalaxyl is a systemic fungicide used to control plant diseases caused by Oomycete fungi. Its formulations include granules, wettable powders, dusts, and emulsifiable concentrates. Application may be by foliar or soil incorporation, surface spraying (broadcast or band), drenching, and seed treatment. Metalaxyl registered products either contain metalaxyl as the sole active ingredient or are combined with other active ingredients (e.g., captan, mancozeb, copper compounds, carboxin). Due to its broad-spectrum activity, metalaxyl is used world-wide on a variety of fruit and vegetable crops. Its effectiveness results from inhibition of uridine incorporation into RNA and specific inhibition of RNA polymerase-1. Metalaxyl has both curative and systemic properties. Its mammalian toxicity is classified as EPA toxicity class III and it is also relatively non-toxic to most nontarget arthropod and vertebrate species. Adequate analytical methods of TLC, GLC, HPLC, MS, and other techniques are available for identification and determination of metalaxyl residues and its metabolites. Available laboratory and field studies indicate that metalaxyl is stable to hydrolysis under normal environmental pH values, It is also photolytically stable in water and soil when exposed to natural sunlight. Its tolerance to a wide range of pH, light, and temperature leads to its continued use in agriculture. Metalaxyl is photodecomposed in UV light, and photoproducts are formed by rearrangement of the N-acyl group to the aromatic ring, demethoxylation, N-deacylation, and elimination of the methoxycarbonyl group from the molecule. Photosensitizers such as humic acid, TiO2, H2O2, acetone, and riboflavin accelerate its photodecomposition. Information is provided on the fate of metalaxyl in plant, soil, water, and animals. Major metabolic routes include hydrolysis of the methyl ester and methyl ether oxidation of the ring-methyl groups. The latter are precursors of conjugates in plants and animals. In soils the most relevant metabolite is the metalaxyl acid, which is formed predominantly by soil microorganisms. Plant uptake, microbial degradation, photodecomposition, and leaching are the major route of metalaxyl dissipation. It has a tendency to migrate to deeper soil horizons with a potential to contaminate groundwater, particularly in soils with low organic matter and clay content. Therefore, precautions should be taken for the continuous application of metalaxyl to crops. If use of metalaxyl is greately increased, the risk of occurrence in groundwater must be reassessed, as by monitoring studies in the most vulnerable areas in main use regions. The R-isomer of metalaxyl (mefenoxam) has recently been registered as the only active compound. Therefore, quantitative studies on the fate of this specific isomer are needed, including appropriate analytical methods. As the use rates of mefenoxam are approximately one-half those recommended for metalaxyl and mefenoxam dissipates more rapidly, concerns for mefenoxam reaching groundwater are even less justified.
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PMID:Metalaxyl: persistence, degradation, metabolism, and analytical methods. 1258 32

Defects in DNA mismatch repair (MMR) are common in human cancers, confer tolerance to certain types of chemotherapeutic agents, and lead to genomic instability. In addition to their mismatch-correcting roles during DNA replication, MMR proteins can bind to certain DNA lesions and signal p53 and apoptosis by an unknown mechanism. To further study the mechanism by which the MMR protein MLH1 is involved in the induction of p53 and apoptosis, we exposed the colon carcinoma cell line HCT116 (MLH1-deficient) and mlh1-corrected HCT116 sublines to alkylating agents or hydrogen peroxide (H2O2). It was found that while alkylating agents induced both apoptosis and phosphorylation of the Ser-15 site of p53 in a MLH1-dependent manner, induction of apoptosis, but not p53 phosphorylation, was MLH1 dependent following treatment with H2O2. The MLH1-dependent induction of p53 phosphorylation by alkylating agents did not appear to be cell cycle dependent, arguing against a futile repair mechanism operating during S phase as the sole mechanism for the MLH1-dependent DNA damage signaling. Importantly, we found that both alkylating agents and H2O2 caused significant inhibition of mRNA synthesis in MLH1-expressing but not in MLH1-deficient cells. These findings suggest a novel mechanism of MLH1 in the induction p53 and apoptosis by inhibiting RNA polymerase II-dependent transcription on damaged DNA templates.
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PMID:Potential role of MLH1 in the induction of p53 and apoptosis by blocking transcription on damaged DNA templates. 1293

The molecular basis of organ specificity in plant diseases is little characterized. Downy mildew of Arabidopsis caused by the oomycete Hyaloperonospora parasitica (formerly Peronospora parasitica) is characteristically a leaf disease. Resistant host genotypes recognize the pathogen in a gene-for-gene dependent manner and respond with the production of H2O2 and the execution of a genetically programmed hypersensitive cell death (HR). We inoculated the roots of Arabidopsis genotypes Col-0, Ws-0, and Wei-0 with the NOCO and WELA races of the pathogen and compared the responses with those observed in leaves. Combinations of incompatible genotypes of host and pathogen showed the expected responses of an oxidative burst and the HR in leaves, but surprisingly, roots showed no signs of active defense and appeared completely susceptible to all the H. parasitica isolates tested. Reverse transcriptase-polymerase chain reaction showed that the R gene RPP1, which mediates resistance in leaves of accession Ws-0 to the H. parasitica isolate NOCO, was expressed in leaves as well as in roots. Similarly, NDR1 and EDS1, two components of R gene-mediated signaling pathways, are also expressed in both tissues. To our knowledge, it has not been previously demonstrated that expression of R genes and downstream components of the signaling cascade are not sufficient for the induction of avirulence gene-mediated defense mechanisms in roots.
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PMID:Organ-specificity in a plant disease is determined independently of R gene signaling. 1297 98

Cl- channels have been implicated in essential cellular functions including volume regulation, progression of cell cycle, cell proliferation and contraction, but the physiological functions of the ClC-3 channel are controversial. We tested the hypothesis that the ClC-3 gene (ClCn-3) is upregulated in hypertensive pulmonary arteries of monocrotaline-treated rats, and upregulated ClC-3 channel aids viability of pulmonary artery smooth muscle cells (PASMCs). Experimental pulmonary hypertension was induced in rats by a single subcutaneous administration of monocrotaline (60 mg kg(-1)). Injected animals developed characteristic features of pulmonary hypertension including medial hypertrophy of pulmonary arteries and right ventricular hypertrophy. Reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and Western immunoblot analysis indicated that histopathological alterations were associated with upregulation of the ClC-3 mRNA and protein expression in both smooth muscle cells of hypertensive pulmonary arteries and in cardiac myocytes. RT-PCR analysis of mRNA, extracted from canine cultured PASMCs, indicated that incubation with the inflammatory mediators endothelin-1 (ET-1), platelet-derived growth factor (PDGF), interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF alpha), but not transforming growth factor beta (TGFbeta), upregulated ClC-3 mRNA. Adenovirus-mediated delivery and overexpression of ClC-3 in canine PASMCs improved cell viability against increasing concentrations of hydrogen peroxide (H2O2, range 50-250 microM). In conclusion, upregulation of ClC-3 in rat hypertensive lung and heart is a novel observation. Our functional data suggest that upregulation of ClC-3 is an adaptive response of inflamed pulmonary artery, which enhances the viability of PASMCs against reactive oxygen species.
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PMID:ClC-3 chloride channel is upregulated by hypertrophy and inflammation in rat and canine pulmonary artery. 1572 95

Diacylglycerol kinase (DGK) plays an important role in signal transduction through modulating the balance between two signaling lipids, diacylglycerol and phosphatidic acid. Here we identified a tenth member of the DGK family designated DGK kappa. The kappa-isozyme (1271 amino acids, calculated molecular mass, 142 kDa) contains a pleckstrin homology domain, two cysteine-rich zinc finger-like structures, and a separated catalytic region as have been found commonly for the type II isozymes previously cloned (DGKdelta and DGKeta). The new DGK isozyme has additionally 33 tandem repeats of Glu-Pro-Ala-Pro at the N terminus. Reverse transcriptase-PCR showed that the DGK kappa mRNA is most abundant in the testis, and to a lesser extent in the placenta. DGK kappa, when expressed in HEK293 cells, was persistently localized at the plasma membrane even in the absence of cell stimuli. Deletion analysis revealed that the short C-terminal sequence (amino acid residues 1199-1268) is necessary and sufficient for the plasma membrane localization. Interestingly, DGK kappa, but not other type II DGKs, was specifically tyrosine-phosphorylated at Tyr78 through the Src family kinase pathway in H2O2-treated cells. Moreover, H2O2 selectively inhibited DGK kappa activity in a Src family kinase-independent manner, suggesting that the isozyme changes the balance of signaling lipids in the plasma membrane in response to oxidative stress. The expression patterns, subcellular distribution, and regulatory mechanisms of DGK kappa are distinct from those of DGKdelta and DGKeta despite high structural similarity, suggesting unique functions of the individual type II isozymes.
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PMID:Identification and characterization of a novel human type II diacylglycerol kinase, DGK kappa. 1621 Mar 24


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