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)

Most eukaryotic genes are transcribed by RNA polymerase II (Pol II), including those that produce mRNAs and many noncoding functional RNAs. Proper expression of these genes requires efficient termination by Pol II to avoid transcriptional interference and synthesis of extended, nonfunctional RNAs. We previously described a pathway for yeast Pol II termination that involves recognition of an element in the nascent transcript by the essential RNA-binding protein Nrd1. The Nrd1-dependent pathway appears to be used primarily for nonpolyadenylated transcripts, such as the small nuclear and small nucleolar RNAs (snoRNAs). mRNAs are thought to use a distinct pathway that is coupled to cleavage and polyadenylation of the transcript. Here we show that the terminator elements for two yeast snoRNA genes also direct polyadenylated 3'-end formation in the context of an mRNA 3' untranslated region. A selection for cis-acting terminator readthrough mutations identified conserved features of these elements, some of which are similar to cleavage and polyadenylation signals. A selection for trans-acting mutations that induce readthrough of both a snoRNA and an mRNA terminator yielded mutations in the Rpb3 and Rpb11 subunits of Pol II that define a remarkably discrete surface on the trailing end of the enzyme. Our results suggest that, at least in budding yeast, protein-coding and noncoding Pol II-transcribed genes use similar mechanisms to direct termination and that the termination signal is transduced through the Rpb3/Rpb11 heterodimer.
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PMID:cis- and trans-Acting determinants of transcription termination by yeast RNA polymerase II. 1653 12

Deleted in Azoospermia Associated Protein 1 (DAZAP1) is a ubiquitous RNA-binding protein highly expressed in the human and the mouse testes. It shows a dynamic subcellular localization during spermatogenesis, present predominantly in the nuclei of late-stage spermatocytes and round spermatids and translocated to the cytoplasm during spermatid elongation. To test the hypothesis that DAZAP1 shuttles between the nucleus and the cytoplasm, we studied the nuclear transport of DAZAP1 in somatic cells using immunostaining, heterokaryon formation, and mutagenesis. DAZAP1 is detected exclusively in the nucleus and has the ability to shuttle between the nucleus and the cytoplasm using a highly conserved 25 amino acid segment, designated ZNS, at its C terminus. ZNS shares no sequence homology with other known nuclear localization or export signals. Attachment of ZNS to a red fluorescent protein DsRed2 confers the nucleocytoplasmic shuttling ability to that protein. The nuclear localization of DAZAP1 depends on active transcription. In the presence of an RNA polymerase II inhibitor, DAZAP1 is retained in the cytoplasm. DAZAP1 colocalizes with hnRNP A1 and hnRNP C1 in the nucleus and is a component of the heterogeneous nuclear ribonucleoprotein particles. Our results suggest that DAZAP1 plays a key role in mRNA transport during spermatogenesis.
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PMID:A novel nucleocytoplasmic shuttling sequence of DAZAP1, a testis-abundant RNA-binding protein. 1677 59

Argonaute proteins are the core components of effector complexes that facilitate RNA interference (RNAi). Small interfering RNAs (siRNAs) targeted to promoter regions mediate transcriptional gene silencing (TGS) in human cells through heterochromatin formation. RNAi effector complexes have yet to be implicated in the mechanism of mammalian TGS. Here we describe the role of the human Argonaute-1 homolog (AGO1) in directing TGS at the promoters for human immunodeficiency virus-1 coreceptor CCR5 and tumor suppressor RASSF1A. AGO1 associates with RNA polymerase II (RNAPII) and is required for histone H3 Lys9 dimethylation and TGS. AGO1, TAR RNA-binding protein-2 (7TRBP2) and Polycomb protein EZH2 colocalize to the siRNA-targeted RASSF1A promoter, implicating Polycomb silencing in the mechanism of mammalian TGS. These results establish a connection between RNAi components AGO1 and TRBP2, RNAPII transcription and Polycomb-regulated control of gene expression.
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PMID:Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. 1693 26

RNA export factor (REF) is a component of the exon junction complex (EJC) that is deposited on mRNA in a splicing-dependent manner, and targets spliced mRNA for export. In this study, analysis of the RNA-binding protein complexes revealed that REF associates with beta-globin mRNA at the region other than the EJC deposition site. Comparison between RNA polymerase II and T7 transcription and further analysis showed that the deposition of REF apart from the EJC is dependent on the 5' cap structure, but not splicing. Excess amounts of m(7)GpppG cap analog reduced REF binding to intronless mRNA, and a co-immunoprecipitation experiment revealed that REF interacts with the cap-binding protein CBP20. The export of Cy3-labeled intronless beta-globin mRNA from nuclei of HeLa cells was enhanced by co-injection of CBP20 and REF. Thus, REF recruited by CBP20 may play a stimulatory role to export the capped intronless mRNAs.
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PMID:The interaction between cap-binding complex and RNA export factor is required for intronless mRNA export. 1736 67

Nuclear factor 90 (NF90) is a double-stranded RNA-binding protein implicated in multiple cellular functions, but with few identified RNA partners. Using in vivo cross-linking followed by immunoprecipitation, we discovered a family of small NF90-associated RNAs (snaR). These highly structured non-coding RNAs of approximately 117 nucleotides are expressed in immortalized human cell lines of diverse lineages. In human tissues, they are abundant in testis, with minor distribution in brain, placenta and some other organs. Two snaR subsets were isolated from human 293 cells, and additional species were found by bioinformatic analysis. Their genes often occur in multiple copies arranged in two inverted regions of tandem repeats on chromosome 19. snaR-A is transcribed by RNA polymerase III from an intragenic promoter, turns over rapidly, and shares sequence identity with Alu RNA and two potential piRNAs. It interacts with NF90's double-stranded RNA-binding motifs. snaR orthologs are present in chimpanzee but not other mammals, and include genes located in the promoter of two chorionic gonadotropin hormone genes. snaRs appear to have undergone accelerated evolution and differential expansion in the great apes.
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PMID:Novel rapidly evolving hominid RNAs bind nuclear factor 90 and display tissue-restricted distribution. 1785 95

In trypanosomes, the apparent lack of regulation of RNA polymerase II-dependent transcription initiation poses a challenge to understand how these eukaryotes adjust gene expression to adapt to the contrasting environments they find during their life cycles. Evidence so far indicates that mRNA turnover and translation are the major control points in which regulation is exerted in trypanosomes. However, very little is known about which proteins are involved, and how do they regulate the abundance and translation of different mRNAs in different life stages. In this work, an RNA-binding protein, TbDRBD3, has been identified by affinity chromatography, and its function addressed using RNA interference, microarray analysis and immunoprecipitation of mRNA-protein complexes. The results obtained indicate that TbDRBD3 binds to a subset of developmentally regulated mRNAs encoding membrane proteins, and that this association promotes the stabilization of the target transcripts. These observations raise the possibility that TbDRBD3-mRNA complexes act as a post-transcriptional operon, and provide a framework to interpret how trypanosomes regulate gene expression in the absence of transcriptional control.
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PMID:The RNA-binding protein TbDRBD3 regulates the stability of a specific subset of mRNAs in trypanosomes. 1861 51

TAF15 (formerly TAF(II)68) is a nuclear RNA-binding protein that is associated with a distinct population of TFIID and RNA polymerase II complexes. TAF15 harbours an N-terminal activation domain, an RNA recognition motif (RRM) and many Arg-Gly-Gly (RGG) repeats at its C-terminal end. The N-terminus of TAF15 serves as an essential transforming domain in the fusion oncoprotein created by chromosomal translocation in certain human chondrosarcomas. Post-transcriptional modifications (PTMs) of proteins are known to regulate their activity, however, nothing is known on how PTMs affect TAF15 function. Here we demonstrate that endogenous human TAF15 is methylated in vivo at its numerous RGG repeats. Furthermore, we identify protein arginine N-methyltransferase 1 (PRMT1) as a TAF15 interactor and the major PRMT responsible for its methylation. In addition, the RGG repeat-containing C-terminus of TAF15 is responsible for the shuttling between the nucleus and the cytoplasm and the methylation of RGG repeats affects the subcellular localization of TAF15. The methylation of TAF15 by PRMT1 is required for the ability of TAF15 to positively regulate the expression of the studied endogenous TAF15-target genes. Our findings demonstrate that arginine methylation of TAF15 by PRMT1 is a crucial event determining its proper localization and gene regulatory function.
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PMID:PRMT1 mediated methylation of TAF15 is required for its positive gene regulatory function. 1912 16

From the moment a nascent transcript emerges from an RNA polymerase until its ultimate destruction, an RNA is bound by proteins that govern its fate. Thus, in order to understand posttranscriptional regulation of gene expression, it is essential to ascertain which proteins bind a given RNA in vivo. This chapter describes three immunoprecipitation-based assays designed to query the in vivo makeup of RNA-protein complexes. Two of these, UV cross-linking and RNA immunoprecipitation (RIP), include cross-linking steps that trap complexes formed in vivo. A third, a cell mixing experiment, verifies that an interaction occurs in vivo by controlling for RNA-protein association subsequent to cell lysis. Using these protocols, this chapter presents evidence that the abundant nuclear RNA-binding protein hnRNP C interacts with the Kaposi's sarcoma-associated herpesvirus polyadenylated nuclear RNA in vivo.
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PMID:Chapter 15. Co-immunoprecipitation techniques for assessing RNA-protein interactions in vivo. 1921 65

The respiratory syncytial virus (RSV) M2-1 protein is an essential cofactor of the viral RNA polymerase complex and functions as a transcriptional processivity and antitermination factor. M2-1, which exists in a phosphorylated or unphosphorylated form in infected cells, is an RNA-binding protein that also interacts with some of the other components of the viral polymerase complex. It contains a CCCH motif, a putative zinc-binding domain that is essential for M2-1 function, at the N terminus. To gain insight into its structural organization, M2-1 was produced as a recombinant protein in Escherichia coli and purified to >95% homogeneity by using a glutathione S-transferase (GST) tag. The GST-M2-1 fusion proteins were copurified with bacterial RNA, which could be eliminated by a high-salt wash. Circular dichroism analysis showed that M2-1 is largely alpha-helical. Chemical cross-linking, dynamic light scattering, sedimentation velocity, and electron microscopy analyses led to the conclusion that M2-1 forms a 5.4S tetramer of 89 kDa and approximately 7.6 nm in diameter at micromolar concentrations. By using a series of deletion mutants, the oligomerization domain of M2-1 was mapped to a putative alpha-helix consisting of amino acid residues 32 to 63. When tested in an RSV minigenome replicon system using a luciferase gene as a reporter, an M2-1 deletion mutant lacking this region showed a significant reduction in RNA transcription compared to wild-type M2-1, indicating that M2-1 oligomerization is essential for the activity of the protein. We also show that the region encompassing amino acid residues 59 to 178 binds to P and RNA in a competitive manner that is independent of the phosphorylation status of M2-1.
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PMID:The respiratory syncytial virus M2-1 protein forms tetramers and interacts with RNA and P in a competitive manner. 1938 1

DNA-damaging agents cause a multifaceted cellular stress response. Cells set in motion either repair mechanisms or programmed cell death pathways, depending on the extent of the damage and on their ability to withstand it. The RNA-binding protein (RBP) Sam68, which is up-regulated in prostate carcinoma, promotes prostate cancer cell survival to genotoxic stress. Herein, we have investigated the function of Sam68 in this cellular response. Mitoxantrone (MTX), a topoisomerase II inhibitor, induced relocalization of Sam68 from the nucleoplasm to nuclear granules, together with several other RBPs involved in alternative splicing, such as TIA-1, hnRNP A1 and the SR proteins SC35 and ASF/SF2. Sam68 accumulation in nuclear stress granules was independent of signal transduction pathways activated by DNA damage. Using BrU labelling and immunofluorescence, we demonstrate that MTX-induced nuclear stress granules are transcriptionally active foci where Sam68 and the phosphorylated form of RNA polymerase II accumulate. Finally, we show that MTX-induced relocalization of Sam68 correlates with changes in alternative splicing of its mRNA target CD44, and that MTX-induced CD44 splicing depends on Sam68 expression. These results strongly suggest that Sam68 is part of a RNA-mediated stress response of the cell that modulates alternative splicing in response to DNA damage.
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PMID:Genotoxic stress causes the accumulation of the splicing regulator Sam68 in nuclear foci of transcriptionally active chromatin. 2011 Feb 58


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