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)

It has been recently suggested that E. coli RNA polymerase can specifically recognize a fork junction DNA structure, suggesting a possible role for such interaction in promoter DNA melting [Guo, Y., and Gralla, J. D. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 11655-11660]. We have determined here quantitatively, using a site-specific binding assay, the effects of base substitutions within the conserved -10 hexamer in the context of a short fork junction DNA on binding to RNA polymerase. Adenine at position -11 and thymine at position -7 were found to be critical for sequence-specific recognition of the DNA. The identities of bases at positions -9 and -8 were found to be not important for the binding whereas replacement of bases at positions -12 and -10 had a mild negative effect on the binding affinity. It was found that for the binding of fork DNA to RNA polymerase, specific sequence recognition was more important than specific recognition of fork junction DNA structure. The pattern of relative importance of bases in the -10 region for binding RNA polymerase was generally consistent with the sequence conservation pattern observed in nature where positions -11 and -7 are the most conserved. Binding experiments with a series of adenine analogues at position -11 revealed that the N1 nitrogen of adenine was a critical determinant for the preference of the adenine at this position, suggesting a mechanism for the nucleation of promoter DNA melting initiation in which RNA polymerase destabilizes duplex DNA by directly competing with the thymine of the A-T base pair for hydrogen bonding to the N1 position of the -11 nontemplate strand adenine.
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PMID:Sequence determinants for the recognition of the fork junction DNA containing the -10 region of promoter DNA by E. coli RNA polymerase. 1101 6

The survival of Escherichia coli was investigated during long-term starvation in rich media. In aerated cultures, E. coli lost the ability to form colonies earlier in NaCl-free Luria broth than in LB medium containing NaCl. Improved survival at low aeration and the sensitivity to hydrogen peroxide in aging cultures indicated a major role for oxidative stress in cell mortality. Mutants in rpoS, lacking the sigmaS subunit of RNA polymerase, showed altered survival in salt-containing media. However, in the absence of NaCl, although these mutants exhibited a massive loss of viability during the first 2 days, this was followed by a stabilization of the number of survivors. The starved culture contained survivors until at least day 9, long after a wild-type strain had completely lost viability. This peculiar behavior suggests that, in rich media of low osmotic pressure, sigmaS helps in short-term survival but hampers long-term survival. Mutants in osmC, a member of the rpoS regulon, also exhibited reduced survival and increased sensitivity to oxidative stress. The biochemical function of the envelope protein OsmC remains unknown, but present data indicated that it participates, directly or indirectly, in the defense against oxidative compounds.
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PMID:Survival of Escherichia coli during long-term starvation: effects of aeration, NaCl, and the rpoS and osmC gene products. 1128 21

A mechanism of activation of protein biosynthesis in hepatocytes was proposed as effected by the conditioned medium of nonparenchymal liver cells incubated in the presence of high density lypoproteins, cortisol, and lypopolysaccharides. It was found that the increase in the biosynthesis rate was associated with the formation of the tetrahydrocortisol-apolipoprotein A-I (THC-apoA-I) complex in macrophages, which display 5 alpha- and 5 beta-reductase activity and are constituents of nonparenchymal liver hepatocytes. Using the small-angle X-ray scattering technique, it was shown that the THC-apoA-I-eukaryotic DNA interaction may break hydrogen bonds between pairs of complementary nucleic bases and cause the formation of single-stranded DNA fragments capable of binding to DNA-dependent RNA polymerase. The interaction is highly cooperative and has a saturating mode, up to six enzyme molecules being bound per DNA molecule.
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PMID:[Effect of tetrahydrocortisol-apolipoprotein A-I complex on RNA polymerase interaction with eukaryotic DNA and the rate of protein biosynthesis in hepatocytes]. 1135 95

Mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) has been shown to play a critical role in mediating the feedback control of MAP kinase cascades in a variety of cellular processes, including proliferation and stress responsiveness. Although MKP-1 expression is induced by a broad array of extracellular stimuli, the mechanisms mediating its induction remain poorly understood. Here we show that MKP-1 mRNA was potently induced by arsenite and ultraviolet light and modestly increased by heat shock and hydrogen peroxide. Interestingly, arsenite also dramatically induces phosphorylation-acetylation of histone H3 at a global level which precedes the induction of MKP-1 mRNA. The transcriptional induction of MKP-1, histone H3 modification, and elevation in MKP-1 mRNA in response to arsenite are all partially prevented by the p38 MAP kinase inhibitor SB203580, suggesting that the p38 pathway is involved in these processes. Finally, analysis of the DNA brought down by chromatin immunoprecipitation (ChIP) reveals that arsenite induces phosphorylation-acetylation of histone H3 associated with the MKP-1 gene and enhances binding of RNA polymerase II to MKP-1 chromatin. ChIP assays following exposure to other stress agents reveal various degrees of histone H3 modification at the MKP-1 chromatin. The differential contribution of p38 and ERK MAP kinases in mediating MKP-1 induction by different stress agents further illustrates the complexity and versatility of stress-induced MKP-1 expression. Our results strongly suggest that chromatin remodeling after stress contributes to the transcriptional induction of MKP-1.
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PMID:Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. 1168 10

Transcription-coupled repair (TCR) efficiently removes a variety of lesions from the transcribed strand of active genes. By allowing rapid resumption of RNA synthesis, the process is of major importance for cellular resistance to transcription-blocking genotoxic damage. Mutations in the Cockayne syndrome group A or B (CSA or CSB) gene result in defective TCR. However, the exact mechanism of TCR in mammalian cells remains to be elucidated. We found that CSA protein is rapidly translocated to the nuclear matrix after UV irradiation. The translocation of CSA was independent of Xeroderma pigmentosum group C, which is specific to the global genome repair subpathway of nucleotide excision repair (NER) and of the core NER factor Xeroderma pigmentosum group A but required the CSB protein. In UV-irradiated cells, CSA protein colocalized with the hyperphosphorylated form of RNA polymerase II, engaged in transcription elongation. The translocation of CSA was also induced by treatment of the cells with cisplatin or hydrogen peroxide, both of which produce damage that is subjected to TCR but not induced by treatment with dimethyl sulfate, which produces damage that is not subjected to TCR. The hydrogen peroxide-induced translocation of CSA was also CSB dependent. These findings establish a link between TCR and the nuclear matrix mediated by CSA.
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PMID:Translocation of Cockayne syndrome group A protein to the nuclear matrix: possible relevance to transcription-coupled DNA repair. 1178 47

The complex formed by tetrahydrocortisol (THC) and apolipoprotein A-I (ApoAI) specifically interacts with eukaryotic DNA from rat liver. Taken together, physical and chemical data and the results of small-angle X-ray scattering analysis show that interaction of the THC-ApoAI complex with eukaryotic DNA results in deformation of the DNA double helix. Single-stranded fragments were demonstrated to cause deformation of the double helix. In this state DNA forms complexes with DNA-dependent RNA polymerase. This interaction is cooperative and of saturating type; up to six enzyme molecules bind with one DNA molecule. The putative site of complex binding with DNA is the sequence CC(GCC)n found in many genes including the human ApoAI gene. An oligonucleotide of this type was synthesized. Its association constant (Ka) was 1.66 x 10(6) M-1. Substitution of THC with cortysol considerably decreases the Ka. We suggest that THC interacting with GC pairs of the binding site forms hydrogen bonds with cytosine, inducing rupture of the bonds within the complementary nucleic base pair.
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PMID:[Interaction of tetrahydrocortisol-apolipoprotein A-I complex with eukaryotic DNA and with single-stranded oligonucleotides]. 1186 20

In an effort to search for mechanistically new and more potent agents than conventional drugs that target AT-rich sequences in double-stranded DNA, we have tested multi(Zn(2+)-cyclen) complexes. Indeed, they selectively bound to poly(dT) sequences to melt the A-T hydrogen bonds; only 2.5 microM or 4 microM of the p-tris(Zn(2+)-cyclen) complex were required to completely melt a 50 microM nucleobase of double-stranded poly(dA) x poly(dT) or poly(dA-dT)(2) at 25 degrees C. The region with seven consecutive T's in native DNA (150 bp) was protected from micrococcal nuclease hydrolysis, as revealed by footprinting assays, with IC(50) values of 2 microM for p-bis(Zn(2+)-cyclen) and 0.5 microM for p-tris(Zn(2+)-cyclen). The high affinity to AT-rich sequences of these Zn(2+)-cyclen complexes matches or surpasses those of the conventional AT-binding drugs distamycin A (IC(50)=2 microM) and DAPI (5 microM). Moreover, the p-tris(Zn(2+)-cyclen) complex selectively binds to the TATA box sequence of the SV40 early promoter to inhibit the binding of the TATA binding protein as effectively as distamycin A, with an IC(50) value of 0.4 microM. In vitro transcription of poly(dA) x poly(dT) using Escherichia coli RNA polymerase was effectively inhibited by p-tris(Zn(2+)-cyclen). The [(3)H]-ATP incorporation into RNA was more strongly blocked (IC(50)=0.8 microM) than the [(3)H]-UTP incorporation (IC(50)=40 microM), a fact indicating that the p-tris(Zn(2+)-cyclen) complex interacts only with the poly(dT) strand in the double-stranded DNA template.
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PMID:New potent agents binding to a poly(dT) sequence in double-stranded DNA: bis(Zn(2+)-cyclen) and tris(Zn(2+)-cyclen) complexes. 1194 5

MntH, a bacterial homolog of mammalian natural resistance associated macrophage protein 1 (Nramp1), is a primary transporter for Mn(2+) influx in Salmonella enterica serovar Typhimurium and Escherichia coli. S. enterica serovar Typhimurium MntH contributes to H(2)O(2) resistance and is important for full virulence. Consistent with its phenotype and function, mntH is regulated at the transcriptional level by both H(2)O(2) and substrate cation. We have now identified three trans-acting regulatory factors and the three corresponding cis-acting mntH promoter motifs that mediate this regulation. In the presence of hydrogen peroxide, mntH is activated by OxyR, acting through an OxyR-binding motif centered just upstream of the likely -35 RNA polymerase-binding site. In the presence of Fe(2+), mntH is repressed primarily by Fur, acting through a Fur-binding motif overlapping the -35 region. In the presence of Mn(2+), mntH is repressed primarily by the Salmonella equivalent of E. coli b0817, a distant homolog of the Bacillus subtilis manganese transport repressor, MntR, acting through an inverted-repeat motif located between the likely -10 polymerase binding site and the ribosome binding site. E. coli b0817 was recently shown to bind the identical inverted-repeat motif in the E. coli mntH promoter and hence has been renamed MntR (S. I. Patzer and K. Hantke, J. Bacteriol. 183:4806-4813, 2001). Using Deltafur, DeltamntR, and Deltafur DeltamntR mutant strains as well as mutations in the Fur- and MntR-binding motif elements, we found that Fe(2+) can also mediate repression through the Mn(2+) repressor MntR.
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PMID:Regulation of Salmonella enterica serovar Typhimurium mntH transcription by H(2)O(2), Fe(2+), and Mn(2+). 1202 30

The Frankia sp. strain ACN14a superoxide dismutase SodF was previously shown to be induced in response to Alnus glutinosa root exudates, and its gene was sequenced. We report here the sequence of the 9-kb genomic segment surrounding the sodF gene and further characterize this gene and its product. Nine ORFs coding for various proteins, such as regulators, acetyl-CoA transferases, and a bacterioferritin A next to the sodF gene, were found. Northern blot analysis showed that the sodF gene was expressed as a major 1-kb transcript, which indicates that it has its own promoter. The sodF gene strongly complemented an Escherichia coli triple mutant (sodA sodB recA), restoring aerobic growth when the gene was expressed from the synthetic tac promoter but when expressed from its own promoter showed only slight rescue, suggesting that it was poorly recognized by the E. coli RNA polymerase. It is noteworthy that this is the first time that a Frankia gene has been reported to complement an E. coli mutant. The superoxide dismutase activity of the protein was inactivated by hydrogen peroxide, indicating that the metal ligand is iron, which is supported by analysis of the protein sequence. Thus, the SodF protein induced in Frankia by root exudates is an iron-containing enzyme similar to the one present in the nodules.
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PMID:Characterization of the sodF gene region of Frankia sp. strain ACN14a and complementation of Escherichia coli sod mutant. 1289 39

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


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