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)

The bacteriophage Mu mom gene encodes a novel DNA modification that protects the viral genome against a wide variety of restriction endonucleases. Expression of mom is subject to a series of unusual regulatory controls. Transcription requires the action of a phage-encoded protein, C, which binds (probably as a dimer) the mom promoter from -33 to -52 (with respect to the transcription start site) in two adjacent DNA major grooves on one face of the helix. No apparent direct interaction between C and the host RNA polymerase (RNAP) is evident; however, C binding alters mom DNA conformation. In the absence of C, RNAP binds the mom promoter at a site that results in transcription in a direction away from the mom gene. The function of this transcription is unknown. An additional layer of transcriptional regulation complexity is due to the fact that the host Dam DNA-(N6-adenine)methyltransferase is required. Dam methylation of three closely spaced upstream GATC sequences is necessary to prevent binding by the host protein, OxyR, which acts as a repressor. Repression is not mediated by inhibition of C binding, but rather through interference with C-mediated recruitment of RNAP to the correct site. Translation of mom is regulated by the phage Com protein. Com is only 62 amino acids long and contains a zinc finger-like structure (coordinated by four cysteine residues) in the amino terminal domain. Com binds mom mRNA 5' to the mom open reading frame, whose translation start signals are contained in a stem-loop translation-inhibition-structure. Com binding to its target site (5' to and adjacent to the translation-inhibition-structure) results in a stable change in RNA secondary structure that exposes the translation start signals.
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PMID:Unusual transcriptional and translational regulation of the bacteriophage Mu mom operon. 1066 35

The expression of mammalian genes is regulated primarily at the level of initiation of transcription. The regulatory structure of the mammalian genes consists of the sequence coding for a protein, a proximal upstream promoter sequence which binds the general (basal) transcription factors and a distant enhancer sequence which binds the inducible transcription factors. The general transcription factors are proteins which combine with the RNA polymerase at the promoter to form the initiation complex. Binding of the inducible transcription factors at short DNA sequences, named response elements, mostly enhances or rarely represses the formation of the initiation complex. Transcription factors share common structural motifs; the most frequent are zinc finger, leucine zipper and helix-loop-helix structures. Inducible transcription factors are activated to bind their target response elements on DNA by protein kinases, by binding of activating or removal of inhibitory factors, or by de novo protein synthesis. Inducible transcription factors are activated by hormones or growth factors addressing a number of genes which share common response elements. Steroid and thyroid hormones combine with intracellular receptors to form active transcription factors. Other transcription factors are activated by protein kinases which are themselves activated by hormones through cell membrane receptors and further cellular signaling paths. Whereas the main level of transcriptional control is the initiation of RNA synthesis, in some instances genes are also regulated by alternative splicing of the primary transcript or control of translation into proteins. Large-scale silencing of genes is mediated by the packing of DNA in highly condensed heterochromatin structures and DNA methylation at cytosines in defined guanine-cytosine (GC)-sequences.
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PMID:Regulation of mammalian gene expression. 1099 80

The structures of non-coding and coding strands in box C of the internal control region (ICR) of Xenopus laevis somatic 5S RNA gene have been examined by circular dichroism (CD) and Raman spectroscopy in the absence and presence of the third zinc finger of transcription factor IIIA (TFIIIA), which binds to the ICR. The non-coding strand exhibits CD signals assignable to a hairpin and an unfolded structure. The presence of the hairpin structure is supported by Raman spectra, gel electrophoresis, and nucleotide deletion experiments. Binding of the zinc finger to the non-coding strand increases the CD signal of hairpin structure, indicating stabilization of the hairpin structure by the zinc finger. In contrast, the corresponding coding strand remains unfolded even in the presence of the zinc finger. The TFIIIA-ICR complex is not only required for initiation of transcription but also lasts during many rounds of transcription of the 5S RNA gene including the ICR (Bogenhagen et al., Cell 28 (1982) 413). TFIIIA may play a role in promoting the transcription by maintaining the unwound non-coding strand in the hairpin structure and leaving the coding strand available for transcription by RNA polymerase.
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PMID:The third zinc finger of TFIIIA stabilizes a hairpin structure of the non-coding strand in the internal control region of 5S RNA gene. 1113 29

We have previously shown that ZNF74, a candidate gene for DiGeorge syndrome, encodes a developmentally expressed zinc finger gene of the Kruppel-associated box (KRAB) multifinger subfamily. Using RACE, RT-PCR, and primer extension on human fetal brain and heart mRNAs, we here demonstrate the existence of six mRNA variants resulting from alternative promoter usage and splicing. These transcripts encode four protein isoforms differing at their N terminus by the composition of their KRAB motif. One isoform, ZNF74-I, which corresponds to the originally cloned cDNA, was found to be encoded by two additional mRNA variants. This isoform, which contains a KRAB motif lacking the N terminus of the KRAB A box, was devoid of transcriptional activity. In contrast, ZNF74-II, a newly identified form of the protein that is encoded by a single transcript and contains an intact KRAB domain with full A and B boxes, showed strong repressor activity. Deconvolution immunofluorescence microscopy using transfected human neuroblastoma cells and nonimmortalized HS68 fibroblasts revealed a distinct subcellular distribution for ZNF74-I and ZNF74-II. In contrast to ZNF74-I, which largely colocalizes with SC-35 in nuclear speckles enriched in splicing factors, the transcriptionally active ZNF74-II had a more diffuse nuclear distribution that is more characteristic of transcriptional regulators. Taken with the previously described RNA-binding activity of ZNF74-I and direct interaction with a hyperphosphorylated form of the RNA polymerase II participating in pre-mRNA processing, our results suggest that the two ZNF74 isoforms exert different or complementary roles in RNA maturation and in transcriptional regulation.
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PMID:Alternative promoter usage and splicing of ZNF74 multifinger gene produce protein isoforms with a different repressor activity and nuclear partitioning. 1131 19

Researchers are investigating aspects of the life cycle of HIV that can be exploited by new drugs. Promising compounds include those that block the fusion of HIV to cells; dextran sulfate is an example of such a drug. Reverse transcriptase inhibitors continue to receive attention, with the focus placed on dealing with the resistance that HIV develops to this class of drugs. Other studies are targeting HIV integrase, an enzyme that integrates HIV genetic material into the host cell's DNA, as the next important target of antiretroviral therapy. Two zinc finger inhibitors are currently in clinical trials, one of which is about to enter phase I/II dose-ranging studies. Finally, several novel protease inhibitors are in development. Pharmacia and Upjohn are developing a protease inhibitor that is relatively easy to make and is active against HIV.
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PMID:New wave antiretrovirals. 1136 38

The antitumor ecteinascidin ET743 has been shown to inhibit the transcriptional activation of a number of genes at nanomolar concentrations. Cell sensitivity to subnanomolar concentrations of the drug has also been shown to specifically depend on the transcription-coupled nucleotide excision repair system. ET743 is known to bind covalently to the minor groove of a DNA double helix in regions comprising selected sets of three consecutive base pairs. Following alkylation of a central guanine, the minor groove is widened and the DNA is bent toward the major groove. We have previously shown that in the resulting adduct the DNA triplet containing the covalently modified guanine bears a strong resemblance to a DNA triplet recognized by a C(2)H(2) zinc finger. We now expand this earlier finding and use simulation methods to show that head-to-tail binding of three ET743 molecules to three adjacent optimal binding sites stabilizes a DNA structure whose conformation is intermediate between A- and B-form DNA. Furthermore, despite the increase in roll at the sites of covalent attachment, no net curvature is apparent in this complex due to cancellation of the localized bends over virtually one turn of the helix. Both observations are in good analogy to findings in zinc finger-DNA complexes. Triplets are virtually superimposable both directly and upon shifting the register one base pair. In this latter case, the central guanine in a triplet alkylated by ET743 corresponds to the third nucleic base in the triplet recognized by a zinc finger of transcription factors such as EGR1 or Sp-1. The DNA conformation found in the ET743-DNA complex is also strongly reminiscent of an RNA-DNA hybrid, as found in the RNA polymerase II elongation complex. The possible biological implications of these findings in relation to the antitumor action of ET743 are discussed.
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PMID:A 3.(ET743)-DNA complex that both resembles an RNA-DNA hybrid and mimicks zinc finger-induced DNA structural distortions. 1183 98

Histone acetyltransferases (HATs) such as CBP and p300 are regarded as key regulators of RNA polymerase II-mediated transcription, but the critical structural features of their HAT modules remain ill defined. The HAT domains of CBP and p300 are characterized by the presence of a highly conserved putative plant homeodomain (PHD) (C4HC3) type zinc finger, which is part of the functionally uncharacterized cysteine-histidine-rich region 2 (CH2). Here we show that this region conforms to the PHD type zinc finger consensus and that it is essential for in vitro acetylation of core histones and the basal transcription factor TFIIE34 as well as for CBP autoacetylation. PHD finger mutations also reduced the transcriptional activity of the full-length CBP protein when tested on transfected reporter genes. Importantly, similar results were obtained on integrated reporters, which reflect a more natural chromatinized state. Taken together, our results indicate that the PHD finger forms an integral part of the enzymatic core of the HAT domain of CBP.
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PMID:The PHD type zinc finger is an integral part of the CBP acetyltransferase domain. 1188 85

The adenovirus large E1A protein activates transcription from early viral promoters by a mechanism that requires a forty amino acid zinc finger activation domain in E1A conserved region 3 (CR3). Recent results indicate that activation by a Gal4 DNA-binding domain-E1A-CR3 fusion requires an interaction between the E1A-CR3 zinc finger and the Sur2 subunit of the mammalian Mediator (of transcription) complex. Although several host proteins have been shown to bind stably to E1A proteins in adenovirus-infected and -transformed cells, an in vivo interaction with Mediator complex subunits has not been described previously. Using immunoprecipitation and gel filtration analyses of nuclear extracts prepared from HeLa cells infected with adenovirus 5 or mutants that express either large or small E1A specifically and from adenovirus 5-transformed cells, we report here that large E1A, but not small E1A, binds to Mediator complex in vivo. Only approximately 1 to 10% of large E1A is bound to Mediator complex at 18 h postinfection and in transformed cells, probably explaining why Mediator complex subunits were not identified among cellular E1A-binding proteins described earlier. Surprisingly, even though extracted Mediator can quantitatively bind to an E1A-CR3 affinity column, only on the order of 1% of cellular Mediator complex is bound by E1A in vivo. Much of the large E1A bound to Mediator in 293 cells is in a stable complex that includes RNA polymerase II, leading us to suggest that the interaction of E1A-CR3 with Mediator stabilizes the interaction of Mediator with the polymerase. This stabilization of the interaction between Mediator and RNA polymerase II may contribute to the mechanism of activation by E1A-CR3.
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PMID:In vivo association of adenovirus large E1A protein with the human mediator complex in adenovirus-infected and -transformed cells. 1218 2

NucC is structurally and functionally homologous to a family of prokaryotic zinc finger transcription factors required for late gene expression in P2- and P4-related bacteriophages. Characterization of these proteins in vitro has been hampered by their relative insolubility and tendency to aggregate. We report here the successful purification of soluble, active, wild-type NucC protein. Purified NucC exhibits site-specific binding to a conserved DNA sequence that is located upstream of NucC-dependent Serratia marcescens promoters and the late promoters of P2-related phages. This sequence is sufficient for binding of NucC in vitro. NucC binding to the S. marcescens nuclease promoter P(nucA) and to the sequence upstream of the P2 late promoter P(F) is accompanied by DNA bending. NucC protects about 25 nucleotides of the P(F) upstream region from DNase I digestion, and RNA polymerase protects the promoter region only in the presence of NucC. Template DNA, RNA polymerase holoenzyme, and purified NucC are the only macromolecular components required for transcription from P(F) in vitro.
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PMID:Purification and in vitro characterization of the Serratia marcescens NucC protein, a zinc-binding transcription factor homologous to P2 Ogr. 1261 44

Bacteriophage lambda gene Q protein and the related proteins of other lambdoid phages are transcription antiterminators that interact both with DNA in the late gene promoter segment and with RNA polymerase subunits. Using hybrids between Q of lambda and the related Q of phage 80, we characterized elements of both Q and DNA that contribute to the DNA binding function. In particular, we found a C-terminal segment of the protein that is responsible for binding specificity and an approximately 15 residue segment on a predicted alpha helix within this segment at which alanine substitutions decrease DNA binding. We identified a six-nucleotide segment located between the -35 and -10 promoter elements that confers binding specificity and is the site of point mutants that impair binding, and we isolated suppressors in lambda Q that restore binding function by increasing the overall binding affinity. We also identified putative zinc finger structures in both proteins.
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PMID:DNA binding regions of Q proteins of phages lambda and phi80. 1515 Feb 48


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