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 have identified a repetitive DNA element in Nectria haematococca mating population VI, isolate T-2. This repetitive sequence has been called Nrs1. DNA hybridization analysis indicates the sequence is found in several isolates of the fungus pathogenic to Pisum sativum. A 2,027-bp clone containing the Nrs1-2 allele contains a long polyA sequence, imperfect RNA polymerase III promoter sequences, multiple inverted repeats, and the potential for extensive secondary structure similar to known RNA polymerase III transcripts and related retroelements. Ten of the 11 HindIII restriction fragments from isolate T-2 DNA that hybridize to Nrs1-2 segregate in a manner consistent with a 1:1 ratio for random ascospore progeny. The 10 restriction fragment length polymorphism (RFLP) loci define three linkage groups and correspond to three chromosome-sized DNAs from T-2 separated by pulsed field gel electrophoresis. Three RFLP loci defined by hybridization to the gene for pisatin demethylase and localized on the 1.6 million base pair (Mb) chromosome were genetically linked to each other and to several Nrs1 loci. These sequences recombined despite the fact that no obvious homolog exists for the 1.6-Mb chromosome in one parent strain. Allelic RFLPs corresponding to the gene sequence of cutinase were unlinked to Nrs1 loci.
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PMID:Nrs1, a repetitive element linked to pisatin demethylase genes on a dispensable chromosome of Nectria haematococca. 858 8

Human small intestine epithelial cells (enterocytes) provide the first site for cytochrome P-450 (CYP)-catalyzed metabolism of orally ingested xenobiotics. The CYP composition of enterocytes could thus affect the potential toxicity or therapeutic efficacy of xenobiotics by modifying systemic uptake. We have characterized human enterocyte CYP composition to enable assessment of its functional roles. An isolation method for enterocytes from human small intestine was developed using EDTA buffer-mediated elution. Villous enterocytes were isolated in high yield, separated from crypt cells. Reverse transcriptase-polymerase chain reaction of total RNA from enterocytes revealed that CYP1A1, 1B1, 2C, 2D6, 2E1, 3A4, and 3A5 mRNA were expressed, but only CYP2C and 3A4 were detectable by Western immunoblotting in enterocyte microsomes from 10 human small intestines, whereas CYP1A1 was weakly detectable in two of eight intestines tested. Microsomal protein content decreased markedly along the small intestine from the duodenum to the ileum, whereas total CYP content and CYP3A4 erythromycin N-demethylase activity increased slightly in progressing from the duodenum to the jejunum and then decreased markedly toward the ileum. Levels of CYP3A4 and 2C protein did not decrease in concert as a function of length along the intestine distally. Maximal CYP content for the 10 intestines varied from 0.06 to 0.18 nmol/mg microsomal protein and maximal CYP3A4 erythromycin N-demethylase activity varied from 0.30 to 0.76 nmol/min/mg microsomal protein. In conclusion, CYP3A4 is the major form of CYP expressed in human small intestine enterocytes, CYP3A5 expression was not detected, CYP2C and, in some intestines, CYP1A1 were expressed. The highest metabolic activity occurred in the proximal intestine.
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PMID:Characterization of human small intestinal cytochromes P-450. 1038 24

The effect of the administration of Thonningia sanguinea (T. S.) on the abundance of individual components of the cytochrome P450 monooxygenase enzyme was examined using Western blotting and competitive reverse-transcriptase-polymerase chain reaction (RT-PCR). We also investigated the time-course of inhibition of T. S. on drug metabolizing enzymes. A single intraperitoneal dose of T. S. extract (5 ml/kg) suppressed CYP, cytochrome b5 and NADPH-CYP reductase activity by 45%, 34% and 22% respectively 24 h after T. S. administration. While T. S. did not have any significant effect on microsomal glutathione S-transferase activity, it inhibited p-nitrophenol hydroxylase (PNPH, CYP2E1) and 7-methoxyresorufin O-demethylase (MROD, CYP 1A2) activities by 37% and 32% respectively at 12 h post-T. S. administration. PNPH, erythromycin N-demethylase (ERDM, CYP 3A1/2) and MROD activities were inhibited by 28-36% 24 h after T. S. injection. Consistent with these observations, the levels of CYP2E1, CYP1A2 and CYP3A2 proteins were also suppressed 24 h post-T. S. administration. While CYP2E1 mRNA was unaffected by T. S. administration, CYP1A2 and CYP3A2 mRNAs were decreased by T. S. Cytosolic glutathione S-transferase activity was increased by 30%, 6 h after T. S injection. These data demonstrate that administration of T. S. differentially affect CYP isoforms in the liver of rats and that T. S. selectively suppresses CYP3A2 and CYP1A2 gene expression.
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PMID:Selective suppression of cytochrome P450 gene expression by the medicinal herb, Thonningia sanguinea in rat liver. 1474 31

Heterochromatin formation is generally thought to result in transcriptional repression of target loci. However, RNAi-mediated heterochromatin assembly requires RNA polymerase II (Pol II) transcription. The mechanism facilitating Pol II accessibility to heterochromatin is unknown. We show that the fission yeast Epe1, a JmjC domain-containing protein and a negative regulator of heterochromatin, is distributed across all major heterochromatic domains and at certain meiotic genes. Remarkably, Epe1 is recruited to heterochromatic loci by the heterochromatin protein Swi6/HP1. Moreover, Epe1 acts in a heterochromatin-specific context to promote Pol II accessibility by counteracting repressive chromatin. This requires Epe1's JmjC domain, although the mechanism utilized might be distinct from other JmjC proteins that possess known demethylase activities. We also find that Epe1 is preferentially recruited to inverted repeats flanking centromeres to restrain the spread of pericentromeric heterochromatin. Our analyses suggest that Swi6/HP1 recruits opposing chromatin-modifying activities, the balancing of which is crucial for heterochromatin maintenance.
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PMID:Swi6/HP1 recruits a JmjC domain protein to facilitate transcription of heterochromatic repeats. 1679 39

Histone methylation is a reversible modification regulated by the antagonistic functions of residue-specific histone methyltransferases and demethylases. Although methylation of histone H3 at lysines 4 and 36 is linked to transcription, the roles of histone demethylases in transcription regulation are not understood. Here we show that overexpression of either Jhd1 or Rph1, two JmjC-domain proteins, bypasses the requirement for the positive elongation factor gene BUR1. Biochemical analysis and chromatin immunoprecipitation experiments indicate that Rph1 functions as a specific demethylase for H3 K36me3 and K36me2, directly regulating Lys(36) methylation in transcribed regions. Both Jhd1 and Rph1 are required for normal levels of RNA polymerase II cross-linking to genes. Taken together, these findings indicate that a general function of histone demethylases for H3 Lys(36) is to promote transcription elongation by antagonizing repressive Lys(36) methylation by Set2.
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PMID:Two Saccharomyces cerevisiae JmjC domain proteins demethylate histone H3 Lys36 in transcribed regions to promote elongation. 1752 56

MRG15 is a conserved chromodomain protein that associates with histone deacetylases (HDACs) and Tip60-containing histone acetyltransferase (HAT) complexes. Here we further characterize MRG15-containing complexes and show a functional link between MRG15 and histone H3K4 demethylase activity in mammalian cells. MRG15 was predominantly localized to discrete nuclear subdomains enriched for Ser(2)-phosphorylated RNA polymerase II, suggesting it is involved specifically with active transcription. Protein analysis of the MRG15-containing complexes led to the identification of RBP2, a JmjC domain-containing protein. Remarkably, over-expression of RBP2 greatly reduced the H3K4 methylation in culture human cells in vivo, and recombinant RBP2 efficiently removed H3K4 methylation of histone tails in vitro. Knockdown of RBP2 resulted in increased H3K4 methylation levels within transcribed regions of active genes. Our findings demonstrate that RBP2 associated with MRG15 complex to maintain reduced H3K4 methylation at transcribed regions, which may ensure the transcriptional elongation state.
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PMID:RBP2 is an MRG15 complex component and down-regulates intragenic histone H3 lysine 4 methylation. 1757 80

Modifications at the N-terminal tails of nucleosomal histones are required for efficient transcription in vivo. We analyzed how H3 histone methylation and demethylation control expression of estrogen-responsive genes and show that a DNA-bound estrogen receptor directs transcription by participating in bending chromatin to contact the RNA polymerase II recruited to the promoter. This process is driven by receptor-targeted demethylation of H3 lysine 9 at both enhancer and promoter sites and is achieved by activation of resident LSD1 demethylase. Localized demethylation produces hydrogen peroxide, which modifies the surrounding DNA and recruits 8-oxoguanine-DNA glycosylase 1 and topoisomeraseIIbeta, triggering chromatin and DNA conformational changes that are essential for estrogen-induced transcription. Our data show a strategy that uses controlled DNA damage and repair to guide productive transcription.
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PMID:DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. 1818 55

We have investigated the chromatin structure of 5S rDNA, a heterochromatic pericentromeric tandemly repeated family, at 2, 3, 4 and 5 days post-germination. Our results revealed a large-scale reorganization of 5S rDNA chromatin that occurs during the first days of development. Unexpectedly, there is a decondensation followed by a 're'condensation of 5S rDNA chromatin, to obtain almost mature nuclei 5 d post-germination. The reorganization of 5S rDNA chromatin is accompanied by a rapid and active demethylation of 5S rDNA mediated by the ROS1 (repressor of silencing 1) demethylase, whereas the plant-specific RNA polymerase IV (Pol IV) is essential to the 5S chromatin 're'condensation. In conclusion, Pol IV and ROS1 collaborate to unlock the 5S rDNA chromatin inherited from the seed, and establish adult features.
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PMID:Interplay of RNA Pol IV and ROS1 during post-embryonic 5S rDNA chromatin remodeling. 1884 69

The nuclear receptor vitamin D receptor (VDR) is known to associate with three vitamin D response element (VDREs)-containing regions within the CDKN1A (p21) gene region. Here we show in MDA-MB453 breast cancer cells that the natural VDR ligand 1alpha,25-dihydroxyvitamin D(3) causes cyclical transcription factor binding and chromatin looping of distal VDREs to the transcription start site (TSS) of the p21 gene, leading to cyclical accumulation of the p21 mRNA. At the chromatin level, association of the mediator protein MED1 precedes both the peaks of VDR binding to VDREs and phosphorylated RNA polymerase (p-Pol II) to the TSS. The loss of co-repressor NCoR1-histone deacetylase (HDAC) 3 complex and inhibitory chromatin looping from VDREs to the TSS are also initial events followed by increased acetylation of histone 3 at lysine 9 at the TSS prior to initiation of transcription. Simultaneous to VDR and p-Pol II peaks, chromatin loops between VDREs and the TSS are formed, and the lysine demethylase LSD1 and the histone acetyltransferase CBP are enriched in both regions. This is followed by a moderate peak in p21 transcript accumulation, repeated in cycles of 45-60 min. The transcript accumulation pattern is disturbed by siRNA inhibition of the mediator protein MED1, LSD1, NCoR1, or various HDACs, whereas CBP appears unnecessary for the response. Inhibition of MED1, HDAC4, or LSD1 by siRNA also attenuates ligand-induced chromatin looping. In conclusion, 1alpha,25-dihydroxyvitamin D(3) regulates p21 transcription by inducing cyclical chromatin looping that depends on both histone deacetylation and demethylation.
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PMID:Cyclical chromatin looping and transcription factor association on the regulatory regions of the p21 (CDKN1A) gene in response to 1alpha,25-dihydroxyvitamin D3. 1912 96

Lenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21(WAF-1) expression. In the present study, we unravel the molecular mechanism responsible for p21(WAF-1) up-regulation using Namalwa cells as a human lymphoma model. We show that the increase of p21(WAF-1) expression is regulated at the transcriptional level through a mechanism independent of p53. Using a combination of approaches, we show that several GC-rich binding transcription factors are involved in pomalidomide-mediated up-regulation of p21(WAF-1). Furthermore, we report that p21(WAF-1) up-regulation is associated with a switch from methylated to acetylated histone H3 on p21(WAF-1) promoter. Interestingly, lysine-specific demethylase-1 (LSD1) silencing reduced both pomalidomide and lenalidomide up-regulation of p21(WAF-1), suggesting that this histone demethylase is involved in the priming of the p21(WAF-1) promoter. Based on our findings, we propose a model in which pomalidomide and lenalidomide modify the chromatin structure of the p21(WAF-1) promoter through demethylation and acetylation of H3K9. This effect, mediated via LSD1, provides GC-rich binding transcription factors better access to DNA, followed by recruitment of RNA polymerase II and transcription activation. Taken together, our results provide new insights on the mechanism of action of pomalidomide and lenalidomide in the regulation of gene transcription, imply possible efficacy in p53 mutated and deleted cancer, and suggest new potential clinical uses as an epigenetic therapy.
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PMID:Pomalidomide and lenalidomide induce p21 WAF-1 expression in both lymphoma and multiple myeloma through a LSD1-mediated epigenetic mechanism. 1973 71


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