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)

Werner syndrome (WS) is a rare autosomal recessive genetic disorder causing premature aging. The gene (WRN) responsible for WS encodes a protein homologous to the RecQ-type helicase. WRN has a nucleolar localization signal and shows intranuclear trafficking between the nucleolus and the nucleoplasm. WRN is recruited into the nucleolus when rRNA transcription is reactivated in quiescent cells. Inhibition of mRNA transcription with alpha-amanitin has no effect on nucleolar localization of WRN whereas inhibition of rRNA transcription with actinomycin D releases WRN from nucleoli, suggesting that nucleolar WRN is closely related to rRNA transcription by RNA polymerase I (RPI). A possible function of WRN on rRNA transcription through interaction with RPI is supported by the results described here showing that WRN is co-immunoprecipitated with an RPI subunit, RPA40. Here we show that WS fibroblasts are characterized by a decreased level of rRNA transcription compared with wild-type cells, and that the decreased level of rRNA transcription in WS fibroblasts recovers when wild-type WRN is exogenously expressed. By contrast, exogenously expressed mutant-type WRN lacking an ability to migrate into the nucleolus fails to stimulate rRNA transcription. These results suggest that WRN promotes rRNA transcription as a component of an RPI-associated complex in the nucleolus.
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PMID:WRN helicase accelerates the transcription of ribosomal RNA as a component of an RNA polymerase I-associated complex. 1197 Nov 79

Escherichia coli DnaG primase is a single-stranded DNA-dependent RNA polymerase. Primase catalyzes the synthesis of a short RNA primer to initiate DNA replication at the origin and to initiate Okazaki fragment synthesis for synthesis of the lagging strand. Primase activity is greatly stimulated through its interaction with DnaB helicase. Here we report a 96-well homogeneous scintillation proximity assay (SPA) for the study of DnaB-stimulated E. coli primase activity and the identification of E. coli primase inhibitors. The assay uses an adaptation of the general priming reaction by employing DnaG primase, DnaB helicase, and ribonucleotidetriphosphates (incorporation of [(3)H]CTP) for in vitro primer synthesis on single-stranded oligonucleotide and M13mp18 DNA templates. The primase product is captured by polyvinyl toluene-polyethyleneimine-coated SPA beads and quantified by counting by beta-scintography. In the absence of helicase as a cofactor, primer synthesis is reduced by 85%. The primase assay was used for screening libraries of compounds previously identified as possessing antimicrobial activities. Primase inhibitory compounds were then classified as direct primase inhibitors or mixed primase/helicase inhibitors by further evaluation in a specific assay for DnaB helicase activity. By this approach, specific primase inhibitors could be identified.
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PMID:Homogenous assays for Escherichia coli DnaB-stimulated DnaG primase and DnaB helicase and their use in screening for chemical inhibitors. 1200 93

The BamHI-J fragment located at 25.8--9.9 map units of the Spodoptera litura multicapsid nucleopolyhedrovirus (SpltMNPV) genome was sequenced. The fragment contained four ORFs, one partial ORF potentially encoding C-terminal of chitinase gene and one partial homologous region (hr). The four ORFs included lef-8 gene, J domain protein gene (bjdp gene), ORF570 and ORF165. The ORF570 revealed 31% identity to the helicase-2 of Lymantria dispar MNPV. The ORF165 was unique to the SpltMNPV. The bjdp gene, reported here for the first time in baculoviruses, was one of J domain family protein genes, and the predicated amino acid sequence possessed a characteristic of J domain protein of other DnaJ proteins at its N-terminus. The lef-8 showed high identities to the homologs of reported baculovirus genomes. As a component of virus-encoded RNA polymerase, the LEF-8 of SpltMNPV had the conserved motif GIKICGIHGQKG near the C-terminal end. Analysis of the LEF-8 phylogenic tree demonstrated SpltMNPV was very closely related to SpliMNPV.
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PMID:Sequence Analysis of the Bam HI-J Fragment of the Spodoptera litura Multicapsid Nucleopolyhedrovirus. 1203 51

The promoter of the helicase gene, including 510 bp upstream of ATG,was cloned and sequenced, and was found that it had both early and late RNA initiation sites. The initiation codon ATG was deleted by using point mutation. Luciferase gene, as a reporter gene, was fused with the promoter region to construct the plsmid pBm hel 510 luc. When pBm hel 510 luc was transfected into Bm-5 and Sf-21 cell lines, the helicase gene promoter was recognized by cellular RNA polymerase and transactivated by viral factors. Baculovirus homologous regions (hrs) act as viral DNA replication start sites, which also have been shown to alter the rate of transcription for cis-linked promoters. BmNPV hr3 was cloned into a downstream site of luc gene, to study the effect of this enhancer on hel 510 promoter activity. The transient expression in transfected insect cell lines and silkworm larvae indicated that hr 3 could enhance the transcriptional level of hel 510 promoter by about 7 000 and 1 000 fold, respectively.
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PMID:Functional Analysis of Helicase Gene Promoter and Homologous Region 3 Enhancer in Bombyx mori Nuclear Polyhedrosis Virus. 1204 Mar 93

DNA helicases are essential for replication of baculoviruses. It was found that the helicase gene promoter of Bombyx mori nuclear polyhedrosis virus, including 510 bp upstream of ATG, had both early and late RNA initiation sites and could be recognized by cellular RNA polymerase. Transient expression assays in uninfected Sf-21 cells indicated that the helicase gene promoter could be classified as a delayed-early gene promoter. Deletion analysis by PCR showed that the regulation region of its basic transcription was mainly within -510 to -410 bp upstream of ATG. However, the basic activity was still detected with a deletion to -98 bp relative to ATG. In the presence of viral factors, deletion between -510 to -410 bp relative to ATG did not significantly reduce the promoter activity compared to the full-length promoter (510 bp). The remarkable reduction in the promoter activity was observed with continuous deletions. It suggests, therefore, that cis-acting elements responsive to viral factors are mainly located within the range of -410 to -309 bp upstream of ATG.
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PMID:[Identification of functional region of helicase gene promoter in Bombyx mori nuclear polyhedrosis virus]. 1219 56

Currently available therapies for the treatment of chronic hepatitis C are effective in half of patients, but are expensive, often poorly tolerated, and unsuitable for certain patient populations. The ideal therapy would be highly effective, orally bioavailable, have minimal side effects, be cost effective, and suitable for the majority of patients with hepatitis C. Recent advances in understanding the replication cycle of hepatitis C virus (HCV) and structural, crystallographic definitions of components of the viral polyprotein have improved the prospects for development of novel therapies. The lack of a small animal model of HCV infection continues to hamper progress in the preclinical evaluation of new antivirals and vaccines. Strategies to enhance response to current therapies include the development of novel interferons and delivery systems, nucleoside analogues that have reduced hemolysis compared with ribavirin, inosine 5' monophosphate dehydrogenase inhibitors, and other immunomodulators that are being evaluated as adjunctive therapy to interferon-based regimens. Compounds in preclinical or early phase human trials include small molecules that inhibit virus specific enzymes (such as the serine proteases, RNA polymerase and helicase), or those that prevent translation initiation (such as antisense molecules and ribozymes). Antifibrotic agents are also being developed in an attempt to prevent disease progression in patients in whom HCV RNA cannot be eradicated. While the advent of these newer compounds represent an exciting phase in the treatment of HCV, their safety and efficacy need to be established. Most of these newer therapies are unlikely to be available for routine clinical use in the next 3 to 5 years.
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PMID:Future therapy of hepatitis C. 1240

PriA protein provides a means to load the DnaB replicative helicase at DNA replication fork and D loop structures, and is therefore a key factor in the rescue of stalled or broken forks and subsequent replication restart. We show that the nucleoid-associated RdgC protein binds non-specifically to single-stranded (ss) DNA and double-stranded DNA. It is also essential for growth of a strain lacking PriA, indicating that it might affect replication fork progression or fork rescue. dnaC suppressors of priA overcome this inviability, especially when RecF, RecO or RecR is inactivated, indicating that RdgC avoids or counters a toxic effect of these proteins. Mutations modifying ssDNA-binding (SSB) protein also negate this toxic effect, suggesting that the toxicity reflects inappropriate loading of RecA on SSB-coated ssDNA, leading to excessive or untimely RecA activity. We suggest that binding of RdgC to DNA limits RecA loading, avoiding problems at replication forks that would otherwise require PriA to promote replication restart. Mutations in RNA polymerase also reduce the toxic effect of RecFOR, providing a further link between DNA replication, transcription and repair.
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PMID:The RdgC protein of Escherichia coli binds DNA and counters a toxic effect of RecFOR in strains lacking the replication restart protein PriA. 1255 73

A common feature in the maturation of linear dsDNA viruses is that the lengthy viral genome is translocated with remarkable velocity into a limited space within a preformed protein shell using ATP as motor energy. Most biomotors, such as myosin, kinesin, DNA-helicase, and RNA polymerase, contain one ATP-binding component that acts processively. An examination of the well-studied dsDNA viruses reveals that DNA packaging motors involve two nonstructural components. Which component of the motor is the integrated processive factor to turn the motor has not been identified. In bacterial virus phi 29, these two components consist of a gp16 protein and an RNA molecule called pRNA. We have previously predicted and recently confirmed that gp16 binds ATP. It is generally believed that gp16 serves as an ATP-binding and processive component to drive the motor. In this article, phi 29 DNA-packaging intermediates were purified in quantity and examined to differentiate the role between gp16 and pRNA. It was found that the pRNA hexamer is an integral motor component, while gp16 is not stably bound. Only one pRNA hexamer, but multiple copies of gp16, were needed to accomplish DNA packaging. pRNA functions continuously during the entire DNA translocation process, suggesting that pRNA is a vital part of the DNA packaging motor.
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PMID:Only one pRNA hexamer but multiple copies of the DNA-packaging protein gp16 are needed for the motor to package bacterial virus phi29 genomic DNA. 1272 31

Chronic hepatitis C virus (HCV) infection is the cause of an emerging global epidemic of chronic liver disease. Current combination therapies are at best 80% efficacious and are often poorly tolerated. Strategies to improve the therapeutic response include the development of novel interferons, nucleoside analogues with reduced haemolysis compared with ribavirin and inosine 5'-monophosphate dehydrogenase inhibitors. Compounds in preclinical or early clinical trials include small molecules that inhibit virus-specific enzymes (such as the serine proteases, RNA polymerase and helicase) or interfere with translation (including anti-sense molecules, iRNA and ribozymes). Advances in understanding HCV replication, obtaining a sub-genomic replicon and contriving potential small animal models, in addition to solving crystallographic structures for the replication enzymes, have improved prospects for developing novel therapies. This review summarizes current and evolving treatments for chronic hepatitis C infection. In addition, progress in HCV targets and drug discovery tools valuable in the search for novel anti-HCV agents is detailed.
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PMID:Hepatitis C virus therapies: current treatments, targets and future perspectives. 1279 May 12

RNA helicase A (RHA) is a member of ATPase/helicase and regulates the transcription through recruitment of Pol II and/or by ATP dependent mechanisms. In CREB-dependent transcription, RHA recruits RNA polymerase (Pol) II to the CREB binding protein (CBP) via the minimal transactivation domain (MTAD). This region is well conserved among RHA homologues, whereas it is unique to RHA. The three conserved tryptophan residues in MTAD are critical for transactivation. To understand the importance of tryptophan residues on transactivation, we generated mutants in which tryptophan residues were replaced by other aromatic, bulky hydrophobic or small hydrophobic amino acids. Substitutions of tryptophan with either bulky hydrophobic or small hydrophobic amino acid decreased transcriptional activity, whereas aromatic residue had no effect. Moreover, these mutants with tryptophan to phenylalanine, activated CREB-dependent transcription. These results indicate that aromatic characteristics of tryptophan residues in MTAD are important for CREB-dependent transcription via RHA.
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PMID:Aromatic residues are required for RNA helicase A mediated transactivation. 1285 13


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