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)

ELL family transcription factors activate the rate of transcript elongation by suppressing transient pausing by RNA polymerase II at many sites along the DNA. ELL-associated factors 1 and 2 (EAF1 and EAF2) bind stably to ELL family members and act as strong positive regulators of their transcription activities. Orthologs of ELL and EAF have been identified in metazoa, but it has been unclear whether such RNA polymerase II elongation factors are utilized in lower eukaryotes. Using bioinformatic and biochemical approaches, we have identified a new Schizosaccharomyces pombe RNA polymerase II elongation factor that is composed of two subunits designated SpELL and SpEAF, which share weak sequence similarity with members of the metazoan ELL and EAF families. Like mammalian ELL-EAF, SpELL-SpEAF stimulates RNA polymerase II transcription elongation and pyrophosphorolysis. In addition, like many yeast RNA polymerase II elongation factors, deletion of the SpELL gene renders S. pombe sensitive to the drug 6-azauracil. Finally, phylogenetic analyses suggest that the SpELL and SpEAF proteins are evolutionarily conserved in many fungi but not in Saccharomyces cerevisiae.
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PMID:Identification and Characterization of a Schizosaccharomyces pombe RNA Polymerase II Elongation Factor with Similarity to the Metazoan Transcription Factor ELL. 1715 Sep 56

Many developmentally regulated genes contain a poised RNA polymerase II (Pol II) at their promoters under conditions where full-length transcripts are undetectable. It has been proposed that the transcriptional activity of such promoters is regulated at the elongation stage of Pol II transcription. In Drosophila, the heat-shock loci expressing the Hsp70 genes have been used as a model for the regulation of the transcriptional activity of poised Pol II. Drosophila ELL (dELL) is a Pol II elongation factor capable of stimulating the rate of transcription both in vivo and in vitro. Although ELL and the elongation factor Elongin A have indistinguishable effects on RNA polymerase in vitro, the loss-of-function studies indicate that these proteins are not redundant in vivo. In this article, we use RNAi to investigate the physiological properties of dELL and a dELL-associated factor (dEaf) in a living organism. Both ELL and Eaf are essential for fly development. dELL is recruited to heat shock loci upon induction, and its presence with Pol II at such loci is required for proper heat-shock gene expression. Consistent with a role in elongation, dELL knockdown reduces the levels of phosphorylated Pol II at heat-shock loci. This study implicates dELL in the expression of loci regulated by Pol II elongation.
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PMID:Regulation of the transcriptional activity of poised RNA polymerase II by the elongation factor ELL. 1856 76

MLL located at 11q23 is fused with a variety of partner genes by recurrent chromosomal translocations in acute leukemias. ELL, the MLL partner gene located on chromosome 19p13.1, encodes an RNA polymerase II transcriptional elongation factor, which also possesses the N-terminal region involved in the inhibition of transcription initiation. Here we report a case of chronic myelomonocytic leukemia (CMML) with a 46,XY,t(11;19)(q23;p13.1) karyotype that transformed to acute myeloid leukemia (AML) without showing any karyotypic evolution. Interphase fluorescent in situ hybridization analysis showed the split MLL signals in 95% of bone marrow cells when the diagnosis of CMML was made and the percentage of blasts was 1.2%. Sequence analysis of reverse-transcriptional polymerase chain reaction product revealed a novel variant form of MLL-ELL transcript in which MLL exon 10 was fused to ELL exon 3. MLL has been fused to ELL exon 2 in all the previously reported MLL-ELL transcripts, which have always been associated with AML. It is deduced that the variant form of MLL-ELL may be defective not only in inhibition of transcription initiation, but also in transcriptional elongation. Thus, a possibility is raised that the unique clinical presentation of the present case with t(11;19)(q23;p13.1) might be related to the variant form of MLL-ELL.
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PMID:A novel variant form of MLL-ELL fusion transcript with t(11;19)(q23;p13.1) in chronic myelomonocytic leukemia transforming to acute myeloid leukemia. 1861 60

Chromosomal translocations involving the MLL gene are associated with infant acute lymphoblastic and mixed lineage leukemia. There are a large number of translocation partners of MLL that share very little sequence or seemingly functional similarities; however, their translocations into MLL result in the pathogenesis of leukemia. To define the molecular reason why these translocations result in the pathogenesis of leukemia, we purified several of the commonly occurring MLL chimeras. We have identified super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4, and several other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 in leukemic cells shows reduction in MLL chimera target gene expression, suggesting that AFF4/SEC could be a key regulator in the pathogenesis of leukemia through many of the MLL partners.
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PMID:AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. 2018 61

The increasing number of chromosomal rearrangements involving the human MLL gene, in combination with differences in clinical behavior and outcome for MLL-rearranged leukemia patients, makes it necessary to reflect on the cancer mechanism and to discuss potential therapeutic strategies. To date, 64 different translocations have been identified at the molecular level. With very few exceptions, most of the identified fusion partner genes encode proteins that display no homologies or functional equivalence. Only the most frequent fusion partners (AF4 family members, AF9, ENL, AF10 and ELL) are involved in the positive transcription elongation factor b-dependent activation cycle of RNA polymerase II. Biological functions remain to be elucidated for the other fusion partners. This minireview tries to sum up some of the available data and mechanisms identified in leukemic stem and leukemic tumor cells and link this information with the known functions of mixed lineage leukemia and certain mixed lineage leukemia fusion partners.
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PMID:Mixed lineage leukemia: roles in human malignancies and potential therapy. 2023 11

The RNA polymerase II (Pol II) elongation factor (ELL) was the first translocation partner of mixed lineage leukaemia (MLL) for which a biochemical function was determined. It was therefore proposed that the regulation of the elongation stage of transcription could be fundamental to MLL-based leukaemogenesis. Recent studies have identified ELL complexed with several of the translocation partners of MLL in a transcriptional super elongation complex (SEC). These studies provide evidence for the importance of the regulation of Pol II elongation in disease pathogenesis and suggest that MLL chimaeras function by licensing Pol II transcription elongation without the appropriate checkpoints.
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PMID:Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis. 2084 54

Promoter-proximal pausing by initiated RNA polymerase II (Pol II) and regulated release of paused polymerase into productive elongation has emerged as a major mechanism of transcription activation. Reactivation of paused Pol II correlates with recruitment of super-elongation complexes (SECs) containing ELL/EAF family members, P-TEFb, and other proteins, but the mechanism of their recruitment is an unanswered question. Here, we present evidence for a role of human Mediator subunit MED26 in this process. We identify in the conserved N-terminal domain of MED26 overlapping docking sites for SEC and a second ELL/EAF-containing complex, as well as general initiation factor TFIID. In addition, we present evidence consistent with the model that MED26 can function as a molecular switch that interacts first with TFIID in the Pol II initiation complex and then exchanges TFIID for complexes containing ELL/EAF and P-TEFb to facilitate transition of Pol II into the elongation stage of transcription.
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PMID:Human mediator subunit MED26 functions as a docking site for transcription elongation factors. 2172 82

Transcriptional regulation of developmentally controlled genes is at the heart of differentiation and organogenesis. In this study, we performed global genomic analyses in murine embryonic stem (ES) cells and in human cells in response to activation signals. We identified an essential role for the ELL (eleven-nineteen lysine-rich leukemia gene)/P-TEFb (positive transcription elongation factor)-containing super elongation complex (SEC) in the regulation of gene expression, including several genes bearing paused RNA polymerase II (Pol II). Paused Pol II has been proposed to be associated with loci that respond rapidly to environmental stimuli. However, our studies in ES cells also identified a requirement for SEC at genes without paused Pol II, which also respond dynamically to differentiation signals. Our findings suggest that SEC is a major class of active P-TEFb-containing complexes required for transcriptional activation in response to environmental cues such as differentiation signals.
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PMID:Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC). 2176 52

The small nuclear RNA (snRNA) genes have been widely used as a model system for understanding transcriptional regulation due to the unique aspects of their promoter structure, selectivity for either RNA polymerase (Pol) II or III, and because of their unique mechanism of termination that is tightly linked with the promoter. Recently, we identified the little elongation complex (LEC) in Drosophila that is required for the expression of Pol II-transcribed snRNA genes. Here, using Drosophila and mammalian systems, we provide genetic and molecular evidence that LEC functions in at least two phases of snRNA transcription: an initiation step requiring the ICE1 subunit, and an elongation step requiring ELL.
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PMID:The little elongation complex functions at initiation and elongation phases of snRNA gene transcription. 2393 80

A gene induction competition assay has recently uncovered new inhibitory activities of two transcriptional cofactors, NELF-A and NELF-B, in glucocorticoid-regulated transactivation. NELF-A and -B are also components of the NELF complex, which participates in RNA polymerase II pausing shortly after the initiation of gene transcription. We therefore asked if cofactors (Cdk9 and ELL) best known to affect paused polymerase could reverse the effects of NELF-A and -B. Unexpectedly, Cdk9 and ELL augmented, rather than prevented, the effects of NELF-A and -B. Furthermore, Cdk9 actions are not blocked either by Ckd9 inhibitors (DRB or flavopiridol) or by two Cdk9 mutants defective in kinase activity. The mode and site of action of NELF-A and -B mutants with an altered NELF domain are similarly affected by wild-type and kinase-dead Cdk9. We conclude that Cdk9 is a new modulator of GR action, that Ckd9 and ELL have novel activities in GR-regulated gene expression, that NELF-A and -B can act separately from the NELF complex, and that Cdk9 possesses activities that are independent of Cdk9 kinase activity. Finally, the competition assay has succeeded in ordering the site of action of several cofactors of GR transactivation. Extension of this methodology should be helpful in determining the site and mode of action of numerous additional cofactors and in reducing unwanted side effects.
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PMID:A kinase-independent activity of Cdk9 modulates glucocorticoid receptor-mediated gene induction. 2455 2


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