Functional Redundancy of Promoter Elements Ensures Efficient Transcription of the Human 7SK Genein vivo

Boyd, Diana C.; Turner, Philip C.; Watkins, Nicholas J.; Gerster, Thomas; Murphy, Shona

doi:10.1006/jmbi.1995.0582

Cited by 21 publications

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“…U1 and U2) and RNA polymerase III (e.g. U6 and 7SK) (4,5) and purified or recombinant PTF functions as a basal transcription factor for both types of snRNA gene (6,7). The pol III-specific core promoters contain an additional TATA-box at Ϫ25, which in this context is responsible for the selective recruitment of pol III (5,8).…”

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“…U6 and 7SK) (4,5) and purified or recombinant PTF functions as a basal transcription factor for both types of snRNA gene (6,7). The pol III-specific core promoters contain an additional TATA-box at Ϫ25, which in this context is responsible for the selective recruitment of pol III (5,8). Insertion of a TATA element into the pol II-transcribed U2 promoter converts it into a predominantly pol III promoter (8), whereas mutation of the 7SK TATA-box reduces pol III transcription and allows snRNA-type transcription by pol II to occur (5).…”

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“…The pol III-specific core promoters contain an additional TATA-box at Ϫ25, which in this context is responsible for the selective recruitment of pol III (5,8). Insertion of a TATA element into the pol II-transcribed U2 promoter converts it into a predominantly pol III promoter (8), whereas mutation of the 7SK TATA-box reduces pol III transcription and allows snRNA-type transcription by pol II to occur (5). TBP is required for transcription of both types of snRNA gene and is likely to be recruited to the TATAless pol II-specific promoters by interaction with PTF binding to the PSE (3).…”

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“…PTF also potentiates direct binding of TBP to the TATA-box of the pol III-specific promoters (9). Because loss of pol III transcription correlates with the loss of TBP binding to the mutated TATA-box (5,10), the differential interaction of TBP with template DNA and the other proteins of the PIC is likely to play a key role in the ultimate recruitment of different polymerases.…”

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BRFU, a TFIIB-like Factor, Is Directly Recruited to the TATA-box of Polymerase III Small Nuclear RNA Gene Promoters through Its Interaction with TATA-binding Protein

Čabart

Murphy

2001

Journal of Biological Chemistry

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template. We have mapped amino acid residues within TBP and domains of BRFU that mediate this interaction. BRFU has no specificity for sequences flanking the TATA-box and also forms a stable complex on the TATA-box of the pol II-specific adenovirus major late promoter (AdMLP). Furthermore, pol III-type transcription can initiate from an snRNA gene promoter containing an AdMLP TATA-box and flanking sequences. Therefore, the polymerase recruitment is not simply determined by the sequence of the TATA-box and immediate flanking sequences.The core promoter regions of human snRNA 1 genes are sufficient to direct low levels of transcription in vitro and contain a binding site, called the proximal sequence element (PSE), for the multisubunit factor PBP/PTF/SNAP c (1-3). The PSE, usually located around Ϫ55, is interchangeable between snRNA gene promoters recognized by RNA polymerase II (e.g. U1 and U2) and RNA polymerase III (e.g. U6 and 7SK) (4, 5) and purified or recombinant PTF functions as a basal transcription factor for both types of snRNA gene (6, 7). The pol III-specific core promoters contain an additional TATA-box at Ϫ25, which in this context is responsible for the selective recruitment of pol III (5,8). Insertion of a TATA element into the pol II-transcribed U2 promoter converts it into a predominantly pol III promoter (8), whereas mutation of the 7SK TATA-box reduces pol III transcription and allows snRNA-type transcription by pol II to occur (5). TBP is required for transcription of both types of snRNA gene and is likely to be recruited to the TATAless pol II-specific promoters by interaction with PTF binding to the PSE (3). PTF also potentiates direct binding of TBP to the TATA-box of the pol III-specific promoters (9). Because loss of pol III transcription correlates with the loss of TBP binding to the mutated TATA-box (5, 10), the differential interaction of TBP with template DNA and the other proteins of the PIC is likely to play a key role in the ultimate recruitment of different polymerases.For transcription of tRNA and 5 S rRNA genes, which have gene-internal pol III promoters, TBP is associated with TFIIIB90 (11) (also called hBRF (12)) and hBЉ (13) (also called TFIIIB150 (14)) within the TFIIIB-␤ complex (15). At these TATA-less promoters, the internal promoter recruits TFIIIC that results in the subsequent recruitment of TFIIIB-␤, which may then directly recruit pol III. TBP is a more loosely associated subunit of the less well characterized snRNA-specific TFIIIB form, designated hTFIIIB-␣ (15), which is required for transcription of the U6/7SK genes by pol III. Recently, a basal transcription factor known as BRFU (13), or TFIIIB50 (14), has been shown to be required for transcription of these snRNA genes but not an adenovirus 2 VA1 gene with an internal pol III promoter. Interestingly, BRFU/TFIIIB50 has sequence homology to both TFIIIB90/BRF and the pol II initiation factor TFIIB. A complex of TFIIIB50 and four tightly associated factors constitutes, together with TBP and TFIIIB150, the complete ...

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BRFU, a TFIIB-like Factor, Is Directly Recruited to the TATA-box of Polymerase III Small Nuclear RNA Gene Promoters through Its Interaction with TATA-binding Protein

Čabart

Murphy

2001

Journal of Biological Chemistry

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“…This example of promoter element redundancy is somewhat uncommon but has been noted previously for a variety of genes. For example, the human 7SK encoding a small nuclear RNA contains two octamer-like elements, both of which must be mutated to block transcription (5), and the killer cell Ig-like receptor promoter contains functionally redundant AP4 sites (35). However, since single mutation of IL-6 RE C (most proximal to the NTPDase2 start site) had no effect on either IL-6-sensitive NTPDase2 promoter activity or protein/DNA interaction, it is likely that any effects mediated at this promoter site are indirect.…”

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IL-6 downregulates transcription of NTPDase2 via specific promoter elements

Jin¹,

Lavoie²,

Sheung³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bile ductular proliferation is markedly upregulated in biliary fibrosis and cirrhosis. However, the mechanisms regulating this upregulation in bile ductular proliferation have not been defined. Recently, we demonstrated that expression of the ectonucleotidase nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/Entpd2) by portal fibroblasts (PF) is a critical regulator of bile ductular proliferation. Since interleukin 6 (IL-6) is markedly upregulated in biliary cirrhosis, our aims were to determine the role and mechanism of IL-6 in the regulation of NTPDase2 by PF. We found that IL-6 downregulated NTPDase2 protein expression in a concentration-dependent and time-dependent fashion but did not alter PF α-smooth muscle actin expression. IL-6 markedly downregulated NTPDase2 mRNA expression. Expression of the IL-6 receptor gp130 but not the IL-6 receptor gp80 was detected in PF. Two transcription start sites were identified in rat Entpd2 by the method of RNA ligase-mediated rapid amplification of 5′ cDNA ends. The minimal promoter construct, but not shorter constructs, was downregulated by IL-6. Three putative IL-6 response elements were identified in silico and mutated. Mutation of all three response elements, but not fewer elements, completely abolished the IL-6 response. Thus IL-6 transcriptionally downregulates NTPDase2 expression by PF via actions at specific promoter elements independently of myofibroblastic differentiation. This effect may represent a novel signaling pathway by which bile ductular proliferation is dys-regulated in biliary cirrhosis and thus provides a potential therapeutic approach for the regulation of bile ductular growth. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptExtracellular nucleotides such as ATP regulate a variety of important cellular functions via activation of specific P2X and P2Y receptors (1,8,18,52). In the liver, P2Y receptors are of particular importance in such diverse processes as bile secretion (12), cell volume autoregulation (53), and cell growth (21, 49). Since P2Y receptor activation has important downstream consequences, the regulation of P2Y receptors is of great interest.One of the primary ways in which P2X and P2Y receptors are regulated is via enzymatic catalysis of extracellular nucleotides, which then limit agonist availability (4). The chief enzymes that mediate this catalytic activity are enzymes of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family (28,38). NTPDase2/CD39L1 is expressed in a variety of tissues, but there are limited observations about its potential physiologic function(s) (31,44). In the healthy liver, NTPDase2 is expressed only in portal fibroblasts (PF), fibrogenic cells that surround intrahepatic bile ducts (11). NTPDase2 is specifically downregulated in biliary cirrhosis in both rats and humans (10). Recently, we demonstrated that NTPDase2 critically regulates bile duct epithelial growth via catalysis of extracellular nucleotides and that this regulation is lost in biliary cirrhosis (21...

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Mechanism of Dioxygen Cleavage in Tetrahydrobiopterin‐Dependent Amino Acid Hydroxylases

Bassan

Blomberg

Siegbahn

2002

Chemistry A European J

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The reaction mechanism for the formation of the hydroxylating intermediate in aromatic amino acid hydroxylases (i.e., phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase) was investigated by means of hybrid density functional theory. These enzymes use molecular oxygen to hydroxylate both the tetrahydrobiopterin cofactor and the aromatic amino acid. A mechanism is proposed in which dioxygen forms a bridging bond between the cofactor and iron. The product is an iron(II)-peroxy-pterin intermediate, and iron was found to be essential for the catalysis of this step. No stable intermediates involving a pterin radical cation and a superoxide ion O(2)(-) were found on the reaction pathway. Heterolysis of the O-O bond in the iron(II)-peroxy-pterin intermediate is promoted by one of the water molecules coordinated to iron and releases hydroxypterin and the high-valent iron oxo species Fe(IV)=O, which can carry out subsequent hydroxylation of aromatic rings. In the proposed mechanism, the formation of the bridging C-O bond is rate-limiting in the formation of Fe(IV)=O.

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Functional Redundancy of Promoter Elements Ensures Efficient Transcription of the Human 7SK Genein vivo

Cited by 21 publications

References 0 publications

BRFU, a TFIIB-like Factor, Is Directly Recruited to the TATA-box of Polymerase III Small Nuclear RNA Gene Promoters through Its Interaction with TATA-binding Protein

BRFU, a TFIIB-like Factor, Is Directly Recruited to the TATA-box of Polymerase III Small Nuclear RNA Gene Promoters through Its Interaction with TATA-binding Protein

IL-6 downregulates transcription of NTPDase2 via specific promoter elements

Mechanism of Dioxygen Cleavage in Tetrahydrobiopterin‐Dependent Amino Acid Hydroxylases

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