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 C-terminal domain (CTD) of the RNA polymerase II (Pol II) largest subunit is hyperphosphorylated during transcription. Using an in vivo cross-linking/chromatin immunoprecipitation assay, we found previously that different phosphorylated forms of RNA Pol II predominate at different stages of transcription. At promoters, the Pol II CTD is phosphorylated at Ser 5 by the basal transcription factor TFIIH. However, in coding regions, the CTD is predominantly phosphorylated at Ser 2. Here we show that the elongation-associated phosphorylation of Ser 2 is dependent upon the Ctk1 kinase, a putative yeast homolog of Cdk9/P-TEFb. Furthermore, mutations in the Fcp1 CTD phosphatase lead to increased levels of Ser 2 phosphorylation. Both Ctk1 and Fcp1 cross-link to promoter and coding regions, suggesting that they associate with the elongating polymerase. Both Ctk1 and Fcp1 have been implicated in regulation of transcription elongation. Our results suggest that this regulation may occur by modulating levels of Ser 2 phosphorylation, which in turn, may regulate the association of elongation factors with the polymerase.
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PMID:Opposing effects of Ctk1 kinase and Fcp1 phosphatase at Ser 2 of the RNA polymerase II C-terminal domain. 1175 37

Basal transcription factor TFIIH phosphorylates the RNA polymerase II (RNApII) carboxy-terminal domain (CTD) within the transcription initiation complex. The catalytic kinase subunit of TFIIH is a member of the cyclin-dependent kinase (Cdk) family, designated Kin28 in Saccharomyces cerevisiae and Cdk7 in higher eukaryotes. Together with TFIIH subunits cyclin H and Mat1, Cdk7 kinase is also found in a trimer complex known as Cdk activating kinase (CAK). A yeast trimer complex has not previously been identified, although a Kin28-Ccl1 dimer called TFIIK has been isolated as a breakdown product of TFIIH. Here we show that a trimeric complex of Kin28-Ccl1-Tfb3 exists in yeast extracts. Several Kin28 point mutants that are defective in CTD phosphorylation were created. Consistent with earlier studies, these mutants have no transcriptional defect in vitro. Like other Cdks, Kin28 is activated by phosphorylation on T162 of the T loop. Kin28 T162 mutants have no growth defects alone but do demonstrate synthetic phenotypes when combined with mutant versions of the cyclin partner, Ccl1. Surprisingly, these phosphorylation site mutants appear to destabilize the association of the cyclin subunit within the context of TFIIH but not within the trimer complex.
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PMID:Kin28 is found within TFIIH and a Kin28-Ccl1-Tfb3 trimer complex with differential sensitivities to T-loop phosphorylation. 1183 96

The human RAD52 protein has been implicated in DNA homologous recombination. Four major functional domains have been identified: a DNA binding domain (amino acids 1-85), a self-association and UBC9-interacting domain (amino acids 85-159), an RPA-interacting domain (amino acids 221-280), and a RAD51-interacting domain (amino acids 287-330). However, it is uncertain about the functional roles of the C-terminal region of RAD52 protein. In this report, we demonstrate an association of a C-terminal domain of human RAD52 (amino acids 302-418) with the XPB and XPD subunits of transcription factor TFIIH and RNA polymerase II (RNAPII). Using a Gal-4 binding based transcription assay, we further show that this C-terminal domain activates transcription. However, the RAD52 self-association domain suppresses transcription, resulting in an overall activity of transcriptional suppression by the full-length RAD52 protein. These results suggest a novel activity of RAD52 in transcription regulation and may further imply a functional role of RAD52 in targeting DNA damage on transcription active loci to recombinational repair.
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PMID:Association of human RAD52 protein with transcription factors. 1237 13

The mammalian Mat1 protein has been implicated in cell cycle regulation as part of the Cdk activating kinase (CAK), and in regulation of transcription as a subunit of transcription factor TFIIH. To address the role of Mat1 in vivo, we have used a Cre/loxP system to conditionally ablate Mat1 in adult mitotic and post-mitotic lineages. We found that the mitotic cells of the germ lineage died rapidly upon disruption of Mat1 indicating an absolute requirement of Mat1 in these cells. By contrast, post-mitotic myelinating Schwann cells were able to attain a mature myelinated phenotype in the absence of Mat1. Moreover, mutant animals did not show morphological or physiological signs of Schwann cell dysfunction into early adulthood. Beyond 3 months of age, however, myelinated Schwann cells in the sciatic nerves acquired a severe hypomyelinating morphology with alterations ranging from cells undergoing degeneration to completely denuded axons. This phenotype was coupled to extensive proliferation and remyelination that our evidence suggests was undertaken by the non-myelinated Schwann cell pool. These results indicate that Mat1 is not essential for the transcriptional program underlying the myelination of peripheral axons by Schwann cells and suggest that the function of Mat1 in RNA polymerase II-mediated transcription in these cells is regulatory rather than essential.
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PMID:Conditional ablation of the Mat1 subunit of TFIIH in Schwann cells provides evidence that Mat1 is not required for general transcription. 1237 59

Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) are genetic disorders with very different clinical features, but all associated with defects in nucleotide excision repair. Defects in the XPA or XPC genes confer sensitivity to UV carcinogenesis in both humans and mice, but only XPA(-/-) mice have increased acute responses to UV exposure, whereas XPC(-/-) mice are normal in this respect. Both XPE and XPF proteins have functions separate from their role in NER, but the exact nature of these functions has not yet been established. The CSA and CSB genes responsible for CS are both components of complexes associated with RNA polymerase II and their role is thought to be in assisting polII in dealing with transcription blocks. XPB and XPD proteins are components of transcription factor TFIIH, which is involved in both basal and activated transcription. XPB is part of the core of TFIIH and has a central role in transcription, whereas XPD connects the core to the CAK subcomplex, and can tolerate many different mutations. Subtle differences in the effects of these different mutations on the many activities of TFIIH and on its stability determine the clinical outcomes, which can be XP, TTD, XP with CS, XP with TTD or COFS. Features of single and double mutant mice indicate that the neurological and ageing features associated with these disorders result from the defects in NER in association with the transcriptional deficiencies. Skin tumours in XP patients have mutations characteristic of UV-induction in the ras, p53 and ptch genes, showing that sunlight-induced mutations in these genes are important in carcinogenesis in XP patients.
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PMID:DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. 1472 16

Mutations in the XPB and XPD helicases of the DNA repair/transcription factor TFIIH are involved in several human genetic disorders. An unanswered problem concerning the complexity of the phenotype-genotype relationship is why mutations in individual subunits of TFIIH produce specific phenotypes and not many others. In order to investigate this question we tested whether mutations in the Drosophila XPB homolog, haywire (hay), would modify homeotic derepression phenotypes. In this work, we report that mutations in hay and in the 140-kDa subunit of the RNA polymerase II (RpII140wimp) act as dominant modifiers of the derepression phenotypes of the Sex combs reduced (Scr) and Ultrabithorax (Ubx) genes. The hay mutations only weakly suppress the Scr derepression phenotype caused by the Antp(Scx) mutation but not by Polycomb. In contrast, the RpII140wimp mutation strongly suppresses both Scr derepression phenotypes. In addition, the RpII140wimp also generates phenotypes indicative of loss of Ubx function. On the other hand, all the derepression homeotic phenotypes are sensitive to the generalized reduction of transcription levels when the flies are grown with actinomycin D. We also show that different promoter control regions have differential sensitivity to different hay alleles. All these results support that although TFIIH is a basal transcription factor, mutations in the subunit encoded by hay have specific effects in the transcription of some genes.
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PMID:RNA polymerase II 140wimp mutant and mutations in the TFIIH subunit XPB differentially affect homeotic gene expression in Drosophila. 1535 95

Rift Valley fever virus (RVFV) causes massive mosquito-borne epidemics among humans and decimates ruminants in which the mortality rate is about 1% and 10-30%, respectively. Morbidity in RVFV-infected humans is high largely due to the effects of hemorrhagic fever and encephalitis. This virus is native to sub-Saharan Africa; yet if this virus is introduced into the environment, virus transmission appears to occur whenever sheep and cattle are present with abundant mosquito populations. RVFV is a negative-strand RNA virus which belongs to the family Bunyaviridae, genus Phlebovirus, and contains tripartite-segmented genomes (S, M, and L). S-segment is the ambisense genome, where N and NSs genes are coded in an antiviral-sense and viral sense S-segment, respectively. The inhibition of host mRNA synthesis, which is induced by the binding of NSs protein to RNA polymerase II transcription factor TFIIH, is the primary reason for the host-protein shut-off in RVFV-infected cells. Development of a RVFV reverse genetics system, which has not been accomplished yet, is important for the study of viral replication mechanisms, host virus interaction, viral pathogenicity as well as vaccine evaluation and development.
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PMID:[Rift Valley fever virus]. 1574 61

Trypanosomatid parasites share a gene expression mode which differs greatly from that of their human and insect hosts. In these unicellular eukaryotes, protein-coding genes are transcribed polycistronically and individual mRNAs are processed from precursors by spliced leader (SL) trans splicing and polyadenylation. In trans splicing, the SL RNA is consumed through a transfer of its 5'-terminal part to the 5' end of mRNAs. Since all mRNAs are trans spliced, the parasites depend on strong and continuous SL RNA synthesis mediated by RNA polymerase II. As essential factors for SL RNA gene transcription in Trypanosoma brucei, the general transcription factor (GTF) IIB and a complex, consisting of the TATA-binding protein-related protein 4, the small nuclear RNA-activating protein complex, and TFIIA, were recently identified. Although T. brucei TFIIA and TFIIB are extremely divergent to their counterparts in other eukaryotes, their characterization suggested that trypanosomatids do form a class II transcription preinitiation complex at the SL RNA gene promoter and harbor orthologues of other known GTFs. TFIIH is a GTF which functions in transcription initiation, DNA repair, and cell cycle control. Here, we investigated whether a T. brucei TFIIH is important for SL RNA gene transcription and found that silencing the expression of the highly conserved TFIIH subunit XPD in T. brucei affected SL RNA gene synthesis in vivo, and depletion of this protein from extract abolished SL RNA gene transcription in vitro. Since we also identified orthologues of the TFIIH subunits XPB, p52/TFB2, and p44/SSL1 copurifying with TbXPD, we concluded that the parasite harbors a TFIIH which is indispensable for SL RNA gene transcription.
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PMID:Spliced leader RNA gene transcription in Trypanosoma brucei requires transcription factor TFIIH. 1725 43

XPB is a superfamily 2 helicase with a 3'-5' polarity. In eukaryotes, XPB is an integral subunit of the transcription factor TFIIH, which plays a dual role in DNA opening at RNA polymerase II promoters and in establishing the repair bubble around a DNA lesion in nucleotide excision repair. Eukaryotic XPB has only very limited helicase activity in vitro and may function as a DNA-dependent molecular switch to catalyse local distortion of DNA in transcription and repair. Most archaea have one or two homologues of the XPB protein with a presumed role in DNA repair, but only one other subunit of the TFIIH complex, the 5'-3' helicase XPD, has been identified in archaea. Here we report the biochemical characterisation of the two homologous XPB proteins from the crenarchaeon Sulfolobus solfataricus. Although both proteins are single-stranded-DNA-stimulated ATPases, neither displays any helicase activity in vitro, consistent with recent studies of eukaryotic XPB. In almost all archaeal genomes, the xpb gene lies adjacent to a conserved partner gene, and we demonstrate that these two gene products form a physical interaction in vitro. We propose the name Bax1 (Binds archaeal XPB) for this protein, which has a predicted endonuclease domain. XPB and Bax1 may collaborate in processing nucleic acid in an archaeal-specific DNA repair pathway.
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PMID:The archaeal XPB protein is a ssDNA-dependent ATPase with a novel partner. 1817 90

XPB, the largest subunit of the eukaryotic transcription factor TFIIH, is essential for both initiation of transcription by RNA polymerase II and nucleotide excision repair (NER). XPB belongs to the SF2 superfamily of monomeric helicases. XPB helicase is thought to have evolved in eukaryotes; however, a gene highly homologous to human XPB can be found in a number of bacteria. This report is the first biochemical characterization of XPB homologues from bacteria, specifically those from Mycobacterium tuberculosis and Kineococcus radiotolerans. Similarly to eukaryotic XPB, bacterial XPB are ATP-dependent 3' --> 5' DNA helicases. The ATPase activity of these XPB helicases is DNA-dependent, requiring a minimum of 4-nucleotide long single-stranded DNA (ssDNA). The maximum rates of ATP hydrolysis are about 10 and 50 molecules per minute by one XPB monomer on a 21-nucleotide ssDNA oligomer and on 5-kb long circular ssDNA, respectively. The ATP hydrolysis by the bacterial XPBs is coupled to their translocation along single-stranded DNA. The hydrolytic activity is strongly dependent on both the nature of a nucleotide triphosphate and that of a divalent metal. The inefficient ATP hydrolysis by bacterial XPB is consistent with nonprocessive functions of its eukaryotic homologue in locally remodeling DNA during transcription initiation and NER.
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PMID:DNA-dependent ATPase activity of bacterial XPB helicases. 1919 47


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