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 prognosis of systemic sclerosis depends chiefly on the extent of the skin lesions, which correlates with the severity of the cardiovascular, pulmonary, and renal manifestations. An erythrocyte sedimentation rate greater than 15-25 mm/h or a hemoglobin level lower than 12.5-11 g/dl is associated with a 2.5- to 3-fold increase in mortality. Anticentromere antibodies are associated with delayed pulmonary hypertension, anti-topoisomerase I antibodies (Scl 70) with interstitial lung disease, and anti-RNA polymerase III antibodies with renovascular hypertension. The risk of death is directly related to the autoantibody pattern. For instance, in a study of 1432 cases from the Pittsburgh Scleroderma Databank, 10-year survival among patients with limited cutaneous disease was 88% in the group with anti-U1-RNP, 75% in the group with anticentromere antibodies, 72% in the group with anti-PmScl, and 65% in the group with anti-Th/To. Ten-year survival in patients with diffuse cutaneous disease was 64% with anti-topoisomerase antibodies, 61% with anti-U3-RNP, and 75% with anti-RNA polymerase III. Several prognostic markers are also available for predicting the risk of organ involvement. For instance, serum levels of KL-6, surfactant proteins SP-A and SP-D, the collagen peptide PIIINP, and homocysteine are associated with the risk of fibrosing alveolitis. Serum levels of CD40L and NP-ProBNP, circulating endothelial cells, and serum anticardiolipin titers correlate with the risk of arterial hypertension. Serum VCAM1 and markers for oxidative stress such as carboxyl terminus residues predict the risk of vascular disease. Other serum markers for organ involvement are under study, although their predictive performance remains to be evaluated.
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PMID:Prognostic markers for systemic sclerosis. 1679 48

In a rare occasion a single chromosomal locus was targeted twice by independent Alu-related retroposon insertions, and in both cases supported neuronal expression of the respective inserted genes encoding small non-protein coding RNAs (npcRNAs): BC200 RNA in anthropoid primates and G22 RNA in the Lorisoidea branch of prosimians. To avoid primate experimentation, we generated transgenic mice to study neuronal expression and protein binding partners for BC200 and G22 npcRNAs. The BC200 gene, with sufficient upstream flanking sequences, is expressed in transgenic mouse brain areas comparable to those in human brain, and G22 gene, with upstream flanks, has a similar expression pattern. However, when all upstream regions of the G22 gene were removed, expression was completely abolished, despite the presence of intact internal RNA polymerase III promoter elements. Transgenic BC200 RNA is transported into neuronal dendrites as it is in human brain. G22 RNA, almost twice as large as BC200 RNA, has a similar subcellular localization. Both transgenically expressed npcRNAs formed RNP complexes with poly(A) binding protein and the heterodimer SRP9/14, as does BC200 RNA in human. These observations strongly support the possibility that the independently exapted npcRNAs have similar functions, perhaps in translational regulation of dendritic protein biosynthesis in neurons of the respective primates.
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PMID:Two primate-specific small non-protein-coding RNAs in transgenic mice: neuronal expression, subcellular localization and binding partners. 1717 35

Antibodies against the N-terminal (NT) but not the basic domain (BD), DNA binding regions of the largest subunit (S1) of RNA polymerase I (RNAPI) were detected in the sera of MRL-lpr/lpr lupus mice. Antibodies against both RNAPI(S1)-NT and -BD, as well as other systemic lupus erythematosus (SLE) autoantigens (La, ribosomal P proteins and Sm/RNP) were produced by rabbits immunized with anti-DNA antibodies that had been affinity purified from SLE patients. Immunization of nonautoimmune mice (Balb/c) with RNAPI(S1)-NT, RNAPI(S1)-BD, or La in the form of GST fusion proteins, induced production of anti-double-stranded (ds) DNA and anti-Sm/RNP. GST-P1 did not induce an anti-dsDNA response in these mice. These results demonstrate that RNAPI(S1)-NT, RNAPI(S1)-BD and La can participate in an anti-autoantigen/anti-DNA antibody loop during an SLE-like autoimmune response.
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PMID:Immunization of nonautoimmune mice with DNA binding domains of the largest subunit of RNA polymerase I results in production of anti-dsDNA and anti-Sm/RNP antibodies. 1736 96

Recent studies have uncovered an unanticipated diversity of noncoding RNAs (ncRNAs), although these studies provide limited insight into their biological significance. Numerous general methods for identification and characterization of protein interactions have been developed, but similar approaches for characterizing cellular ncRNA interactions are lacking. Here we describe RNA Affinity in Tandem (RAT), an original, entirely RNA tag-based method for affinity purification of endogenously assembled RNP complexes. We demonstrate the general utility of RAT by isolating RNPs assembled in vivo on ncRNAs transcribed by RNA polymerase II or III. Using RAT in conjunction with protein identification by mass spectrometry and protein-RNA interaction assays, we define and characterize previously unanticipated protein subunits of endogenously assembled human 7SK RNPs. We show that 7SK RNA resides in a mixed population of RNPs with different protein compositions and responses to cellular stress. Depletion of a newly identified 7SK RNP component, hnRNP K, alters the partitioning of 7SK RNA among distinct RNPs. Our results establish the utility of a generalizable RNA-based RNP affinity purification method and provide insight into 7SK RNP dynamics.
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PMID:RNA-based affinity purification reveals 7SK RNPs with distinct composition and regulation. 1745 62

In amphibian oocytes, most lateral loops of the lampbrush chromosomes correspond to active transcriptional sites for RNA polymerase II. We show that newly assembled small nuclear ribonucleoprotein (RNP [snRNP]) particles, which are formed upon cytoplasmic injection of fluorescently labeled spliceosomal small nuclear RNAs (snRNAs), target the nascent transcripts of the chromosomal loops. With this new targeting assay, we demonstrate that nonfunctional forms of U1 and U2 snRNAs still associate with the active transcriptional units. In particular, we find that their association with nascent RNP fibrils is independent of their base pairing with pre-messenger RNAs. Additionally, stem loop I of the U1 snRNA is identified as a discrete domain that is both necessary and sufficient for association with nascent transcripts. Finally, in oocytes deficient in splicing, the recruitment of U1, U4, and U5 snRNPs to transcriptional units is not affected. Collectively, these data indicate that the recruitment of snRNPs to nascent transcripts and the assembly of the spliceosome are uncoupled events.
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PMID:Splicing-independent recruitment of spliceosomal small nuclear RNPs to nascent RNA polymerase II transcripts. 1784 69

The viral RNA polymerase complex of influenza A virus consists of three subunits PB1, PB2 and PA. Recently, the cellular chaperone Hsp90 was shown to play a role in nuclear import and assembly of the trimeric polymerase complex by binding to PB1 and PB2. Here we show that Hsp90 inhibitors, geldanamycin or its derivative 17-AAG, delay the growth of influenza virus in cell culture resulting in a 1-2 log reduction in viral titre early in infection. We suggest that this is caused by the reduced half-life of PB1 and PB2 and inhibition of nuclear import of PB1 and PA which lead to reduction in viral RNP assembly. Hsp90 inhibitors may represent a new class of antiviral compounds against influenza viruses.
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PMID:Hsp90 inhibitors reduce influenza virus replication in cell culture. 1857 Sep 72

The influenza virus RNA polymerase transcribes the negative-sense viral RNA segments (vRNA) into mRNA and replicates them via complementary RNA (cRNA) intermediates into more copies of vRNA. It is not clear how the relative amounts of the three RNA products, mRNA, cRNA and vRNA, are regulated during the viral life cycle. We found that in viral ribonucleoprotein (vRNP) reconstitution assays involving only the minimal components required for viral transcription and replication (the RNA polymerase, the nucleoprotein and a vRNA template), the relative levels of accumulation of RNA products differed from those observed in infected cells, suggesting a regulatory role for additional viral proteins. Expression of the viral NS2/NEP protein in RNP reconstitution assays affected viral RNA levels by reducing the accumulation of transcription products and increasing the accumulation of replication products to more closely resemble those found during viral infection. This effect was functionally conserved in influenza A and B viruses and was influenza-virus-type-specific, demonstrating that the NS2/NEP protein changes RNA levels by specific alteration of the viral transcription and replication machinery, rather than through an indirect effect on the host cell. Although NS2/NEP has been shown previously to play a role in the nucleocytoplasmic export of viral RNPs, deletion of the nuclear export sequence region that is required for its transport function did not affect the ability of the protein to regulate RNA levels. A role for the NS2/NEP protein in the regulation of influenza virus transcription and replication that is independent of its viral RNP export function is proposed.
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PMID:NS2/NEP protein regulates transcription and replication of the influenza virus RNA genome. 1926 57

Accumulating evidence suggests that regulation of RNA processing through an RNP-driven mechanism is important for coordinated gene expression. This hypothesis predicts that defects in RNP biogenesis will adversely affect the elaboration of specific gene expression programs. To explore the role of RNP biogenesis on mammalian development, we have characterized the phenotype of mice hypomorphic for Thoc1. Thoc1 encodes an essential component of the evolutionarily conserved TREX complex. TREX accompanies the elongating RNA polymerase II and facilitates RNP assembly and recruitment of RNA processing factors. Hypomorphic Thoc1 mice are viable despite significantly reduced Thoc1 expression in the tissues examined. While most tissues of Thoc1-deficient mice appear to develop and function normally, gametogenesis is severely compromised. Male infertility is associated with a loss in spermatocyte viability and abnormal endocrine signaling. We suggest that loss of spermatocyte viability is a consequence of defects in the expression of genes required for normal differentiation of cell types within the testes. A number of the genes affected appear to be direct targets for regulation by Thoc1. These findings support the notion that Thoc1-mediated RNP assembly contributes to the coordinated expression of genes necessary for normal differentiation and development in vivo.
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PMID:Thoc1 deficiency compromises gene expression necessary for normal testis development in the mouse. 1930 11

Much of the complex process of RNP biogenesis takes place at the gene cotranscriptionally. The target for RNA binding and processing factors is, therefore, not a solitary RNA molecule but, rather, a transcription elongation complex (TEC) comprising the growing nascent RNA and RNA polymerase traversing a chromatin template with associated passenger proteins. RNA maturation factors are not the only nuclear machines whose work is organized cotranscriptionally around the TEC scaffold. Additionally, DNA repair, covalent chromatin modification, "gene gating" at the nuclear pore, Ig gene hypermutation, and sister chromosome cohesion have all been demonstrated or suggested to involve a cotranscriptional component. From this perspective, TECs can be viewed as potent "community organizers" within the nucleus.
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PMID:"Cotranscriptionality": the transcription elongation complex as a nexus for nuclear transactions. 1985 29

Myotonic dystrophy type 2 (DM2) is a dominantly inherited autosomal disease with multi-systemic clinical features and it is caused by expansion of a CCTG tetranucleotide repeat in the first intron of the zinc finger protein 9 (ZNF9) gene in 3q21.The expanded-CCUG-containing transcripts are retained in the cell nucleus and accumulate in the form of focal aggregates which specifically sequester the muscleblind-like 1 (MBNL1) protein, a RNA binding factor involved in the regulation of alternative splicing. The structural organization and composition of the foci are still incompletely known. In this study, the nuclear foci occurring in cultured myoblasts from DM2 patients were characterised at fluorescence and transmission electron microscopy by using a panel of antibodies recognizing transcription and processing factors of pre-mRNAs. MBNL1 proved to co-locate in the nuclear foci with snRNPs and hnRNPs, whereas no co-location was observed with RNA polymerase II, the non-RNP splicing factor SC35, the cleavage factor CStF and the PML protein. At electron microscopy the MBNL1-containing nuclear foci appeared as roundish domains showing a rather homogeneous structure and proved to contain snRNPs and hnRNPs. The sequestration of splicing factors involved in early phases of pre-mRNA processing supports the hypothesis of a general alteration in the maturation of several mRNAs, which could lead to the multiple pathological dysfunctions observed in dystrophic patients.
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PMID:RNA/MBNL1-containing foci in myoblast nuclei from patients affected by myotonic dystrophy type 2: an immunocytochemical study. 1986 9


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