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)

Recent studies have revealed that the general transcription factor TFIIH is also a general excision repair factor which, along with several other proteins, is required for transcription-independent excision reaction. As a general transcription factor, TFIIH is recruited to RNA polymerase II-promoter complex by another general transcription factor called TFIIE. We were interested in knowing whether TFIIE is also involved in recruiting TFIIH to the excision repair complex. We found that cell-free extract depleted of TFIIE carried out excision repair at a normal rate, leading us to conclude that TFIIE is not involved in recruiting TFIIH to the damage site and has no role in general excision repair. In contrast, the human damage recognition protein XPA specifically binds to TFIIH and apparently recruits it to the damage site. The carboxyl-terminal half of XPA is responsible for specific interaction with TFIIH. The C261S/C264S mutant of XPA bound the ERCC1-XPF complex normally, but failed to bind TFIIH and failed to complement an XP-A mutant cell-free extract indicating that the XPA-TFIIH interaction is essential to effecting the excision reaction. Interestingly, XPA also binds to the p34 subunit of TFIIE specifically and in competition with the p56 subunit of TFIIE. This latter interaction has no apparent role in general excision repair but may be relevant in the transcription-coupled repair reaction.
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PMID:The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor. 787 63

Phosphorylation of the COOH-terminal domain (CTD) of the largest subunit of RNA polymerase II by general transcription factor IIH (TFIIH) is believed to control the activity of polymerase at some stage of messenger RNA synthesis. In a recent study, transcription factor IIE (TFIIE) was proposed to play a key role in regulating phosphorylation of the RNA polymerase II CTD, on the basis of evidence indicating that preparations of recombinant TFIIE strongly stimulate CTD phosphorylation by TFIIH (Lu, H., Zawel, L., Fischer, L., Egly, J.-M., and Reinberg, D. (1992) Nature 358, 641-645). TFIIE is a heterodimer composed of 56-kDa (p56) and 34-kDa (p34) subunits and functions in concert with the TATA factor, TFIIB, TFIIF, and TFIIH to promote formation of the RNA polymerase II preinitiation complex. In the process of investigating the role that TFIIE plays in controlling phosphorylation of the RNA polymerase II CTD, we discovered that preparations of the recombinant TFIIE p56 subunit were sufficient to reconstitute stimulation of CTD phosphorylation by the TFIIH kinase. Further investigation revealed that CTD kinase stimulatory activity was chromatographically separable from the bulk of the transcriptionally active p56 subunit and was associated, instead, with a minor oligomeric form of p56. Taken together, these findings argue that the TFIIE p56 subunit is capable of interacting not only with the p34 subunit but also with itself to form either heterodimers or high molecular mass oligomers that play distinct roles in transcription initiation and regulation of the TFIIH kinase.
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PMID:An oligomeric form of the large subunit of transcription factor (TF) IIE activates phosphorylation of the RNA polymerase II carboxyl-terminal domain by TFIIH. 805 Nov 77

The human BTF2 (TFIIH) transcription factor is a multisubunit protein involved in transcription initiation by RNA polymerase II (B) as well as in DNA repair. In addition to the previously characterized p62 and p89/ERCC3 subunits, we have cloned two other subunits of BTF2, p44 and p34. The gene encoding p44 appeared to be the human counterpart of SSL1, a gene involved in translation and UV resistance in yeast. Interestingly, the p34 subunit also has homology with a domain of SSL1, suggesting that it corresponds to an as yet unidentified protein involved in DNA repair. Both p44 and p34 possess zinc finger domains that may mediate BTF2 binding to nucleic acids.
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PMID:p44 and p34 subunits of the BTF2/TFIIH transcription factor have homologies with SSL1, a yeast protein involved in DNA repair. 819 29

Saccharomyces cerevisiae cells harboring the temperature-sensitive mutation rpo21-4, in the gene encoding the largest subunit of RNA polymerase II, were shown to be partially impaired for cell-cycle progress at a permissive temperature, and to become permanently blocked at the cell-cycle regulatory step, START, at a restrictive temperature. The rpo21-4 mutation was lethal in combination with cdc28 mutations in the p34 protein kinase gene required for START. Transcripts of the CLN1 and CLN2 genes, encoding G1-cyclin proteins that, along with p34, are necessary for START, were decreased in abundance by the rpo21-4 mutation at a restrictive temperature. Increased G1-cyclin production, by expression of the CLN1 or CLN2 genes from a heterologous GAL promoter, overcame the rpo21-4-mediated START inhibition, but such mutant cells nevertheless remained unable to proliferate at a restrictive temperature. These findings reveal that START can be particularly sensitive to an impaired RNA polymerase II function, presumably through effects on G1-cyclin expression.
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PMID:An impaired RNA polymerase II activity in Saccharomyces cerevisiae causes cell-cycle inhibition at START. 824 87

The human basal transcription factor TFIIH plays a central role in two distinct processes. TFIIH is an obligatory component of the RNA polymerase II (RNAP II) transcription initiation complex. Additionally, it is believed to be the core structure around which some if not all the components of the nucleotide excision repair (NER) machinery assemble to constitute a nucleotide excision repairosome. At least two of the subunits of TFIIH (XPB and XPD proteins) are implicated in the disease xeroderma pigmentosum (XP). We have exploited the availability of the cloned XPB, XPD, p62, p44, and p34 genes (all of which encode polypeptide subunits of TFIIH) to examine interactions between in vitro-translated polypeptides by co-immunoprecipitation. Additionally we have examined interactions between TFIIH components, the human NER protein XPG, and the CSB protein which is implicated in Cockayne syndrome (CS). Our analyses demonstrate that the XPB, XPD, p44, and p62 proteins interact with each other. XPG protein interacts with multiple subunits of TFIIH and with CSB protein.
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PMID:Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein. 865 57

Transcription factor IIH (TFIIH) is a multisubunit protein complex essential for both the initiation of RNA polymerase class II (pol II)-catalyzed transcription and nucleotide excision repair of DNA. Recent studies have shown that TFIIH copurifies with the cyclin-dependent kinase (cdk)-activating kinase complex (CAK) that includes cdk7, cyclin H, and p36/MAT1. Here we report the isolation of two TFIIH-related complexes: TFIIH* and ERCC2/CAK. TFIIH* consists of a subset of the TFIIH complex proteins including ERCC3 (XPB), p62, p44, p41, and p34 but is devoid of detectable levels of ERCC2 (XPD) and CAK. ERCC2/CAK was isolated as a complex that exhibits CAK activity that cosediments with the three CAK components (cdk7, cyclin H, and p36/MAT1) as well as the ERCC2 (XPD) protein. TFIIH* can support pol II-catalyzed transcription in vitro with lower efficiency compared with TFIIH. This TFIIH*-dependent transcription reaction was stimulated by ERCC2/CAK. The ERCC2/CAK and TFIIH* complexes are each active in DNA repair as shown by their ability to complement extracts prepared from ERCC2 (XPD)- and ERCC3 (XPB)-deficient cells, respectively, in supporting the excision of DNA containing a cholesterol lesion. These data suggest that TFIIH* and ERCC2/CAK interact to form the TFIIH holoenzyme capable of efficiently assembling the pol II transcription initiation complex and directly participating in excision repair reactions.
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PMID:Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH. 869 41

Transcription is coupled to repair in Escherichia coli and in humans. Proteins encoded by the mfd gene in E. coli and by the ERCC6/CSB gene in humans, both of which possess the so-called helicase motifs, are required for the coupling reaction. It has been shown that the Mfd protein is an ATPase but not a helicase and accomplishes coupling, in part, by disrupting the ternary complex of E. coli RNA polymerase stalled at the site of DNA damage. In this study we overproduced the human CSB protein using the baculovirus vector and purified and characterized the recombinant protein. CSB has an ATPase activity that is stimulated strongly by DNA; however, it neither acts as a helicase nor does it dissociate stalled RNA polymerase II, suggesting a coupling mechanism in humans different from that in prokaryotes. CSB is a DNA-binding protein, and it also binds to XPA, TFIIH, and the p34 subunit of TFIIE. These interactions are likely to play a role in recruiting repair proteins to ternary complexes formed at damage sites.
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PMID:Human transcription-repair coupling factor CSB/ERCC6 is a DNA-stimulated ATPase but is not a helicase and does not disrupt the ternary transcription complex of stalled RNA polymerase II. 899 76

The transcription/DNA repair factor TFIIH consists of nine subunits, several exhibiting known functions: helicase/ATPase, kinase activity and DNA binding. Three subunits of TFIIH, cdk7, cyclin H and MAT1, form a ternary complex, cdk-activating kinase (CAK), found either on its own or as part of TFIIH. In the present work, we demonstrate that purified human CAK complex (free CAK) and recombinant CAK (rCAK) produced in insect cells exhibit a strong preference for the cyclin-dependent kinase 2 (cdk2) over a ctd oligopeptide substrate (which mimics the carboxy-terminal domain of the RNA polymerase II). In contrast, TFIIH preferentially phosphorylates the ctd as well as TFIIE alpha, but not cdk2. TFIIH was resolved into four subcomplexes: the kinase complex composed of cdk7, cyclin H and MAT1; the core TFIIH which contains XPB, p62, p52, p44 and p34; and two other subcomplexes in which XPD is found associated with either the kinase complex or with the core TFIIH. Using these fractions, we demonstrate that TFIIH lacking the CAK subcomplex completely recovers its transcriptional activity in the presence of free CAK. Furthermore, studies examining the interactions between TFIIH subunits provide evidence that CAK is integrated within TFIIH via XPB and XPD.
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PMID:Substrate specificity of the cdk-activating kinase (CAK) is altered upon association with TFIIH. 913 Jul 8

Genes for the Tfb2, Tfb3, and Tfb4 subunits of yeast RNA polymerase transcription factor IIH (TFIIH) are described. All three genes are essential for cell viability, and antibodies against Tfb3 specifically inhibit transcription in vitro. A C-terminal deletion of Tfb2 caused a defect in nucleotide excision repair, as shown by UV sensitivity of the mutant strain and loss of nucleotide excision repair activity in cell extracts (restored by the addition of purified TFIIH). An interaction between Tfb3 and the Kin28 subunit of TFIIH was detected by the two-hybrid approach, consistent with a role for Tfb3 in linking kinase and core domains of the factor. The deduced amino acid sequence of Tfb2 is similar to that of the 52-kDa subunit of human TFIIH, while Tfb3 is identified as a RING finger protein homologous to the 36-kDa subunit of murine CAK (cyclin-dependent kinase activating kinase) and to the 32-kDa subunit of human TFIIH. Tfb4 is homologous to p34 of human TFIIH and is identified as the weakly associated 37-kDa subunit of the yeast factor. These and other findings reveal a one-to-one correspondence and high degree of sequence similarity between the entire set of yeast and human TFIIH polypeptides.
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PMID:Genes for Tfb2, Tfb3, and Tfb4 subunits of yeast transcription/repair factor IIH. Homology to human cyclin-dependent kinase activating kinase and IIH subunits. 923 28

The acetylation of histones increases the accessibility of nucleosomal DNA to transcription factors [1,2], relieving transcriptional repression [3] and correlating with the potential for transcriptional activity in vivo [4 - 7]. The characterization of several novel histone acetyltransferases - including the human GCN5 homolog PCAF (p300/CBP-associated factor) [8], the transcription coactivator p300/CBP [9], and TAFII250 [10] - has provided a potential explanation for the relationship between histone acetylation and transcriptional activation. In addition to histones, however, other components of the basal transcription machinery might be acetylated by these enzymes and directly affect transcription. Here, we examine the acetylation of the basal transcriptional machinery for RNA polymerase II by PCAF, p300 and TAFII250. We find that all three acetyltransferases can direct the acetylation of TFIIEbetaand TFIIF, and we identify a preferred site of acetylation in TFIIEbeta. Human TFIIE consists of two subunits, alpha(p56) and beta(p34), which form a heterotetramer (alpha2 beta2) in solution ([11], reviewed in [12]). TFIIE enters the preinitiation complex after RNA polymerase II and TFIIF, suggesting that TFIIE may interact directly with RNA polymerase II and/or TFIIF [13,14]. In addition, TFIIE can facilitate promoter melting either in the presence or absence of TFIIH and can stimulate TFIIH-dependent phosphorylation of the carboxy-terminal domain of RNA polymerase II [15-18]. TFIIF has an essential role in both transcription initiation and elongation ([19,20], for review see [21]). We discuss the implications of the acetylation of TFIIEbetaand TFIIF for transcriptional control by PCAF, p300 and TAFII250.
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PMID:Acetylation of general transcription factors by histone acetyltransferases. 928 13


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