Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P23193 (transcription elongation factor)
 739 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chimeric proteins joining the histone methyltransferase MLL with various fusion partners trigger distinctive lymphoid and myeloid leukemias. Here, we immunopurified proteins associated with ENL, a protein commonly fused to MLL. Identification of these ENL-associated proteins (EAPs) by mass spectrometry revealed enzymes with a known role in transcriptional elongation (RNA polymerase II C-terminal domain kinase [RNAPolII CTD] positive transcription elongation factor b [pTEFb]), and in chromatin modification (histone-H3 methyltransferase DOT1L) as well as other frequent MLL partners (AF4, AF5q31, and LAF4), and polycomb group members (RING1, CBX8, and BCoR). The composition of EAP was further verified by coimmunoprecipitation, 2-hybrid analysis, pull-down, and colocalization experiments. Purified EAP showed a histone H3 lysine 79-specific methylase activity, displayed a robust RNAPolII CTD kinase function, and counteracted the effect of the pTEFb inhibitor 5,6-dichloro-benzimidazole-riboside. In vivo, an ENL knock-down diminished genome-wide as well as gene-specific H3K79 dimethylation, reduced global run-on elongation, and inhibited transient transcriptional reporter activity. According to structure-function data, DOT1L recruitment was important for transformation by the MLL-ENL fusion derivative. These results suggest a function of ENL in histone modification and transcriptional elongation.
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PMID:A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. 1785 33

Promoter clearance and transcriptional processivity in eukaryotic cells are fundamentally regulated by the phosphorylation of the carboxy-terminal domain of RNA polymerase II (RNAPII). One of the kinases that essentially performs this function is P-TEFb (positive transcription elongation factor b), which is composed of cyclin-dependent kinase 9 (CDK9) associated with members of the cyclin T family. Here we show that cellular GCN5 and P/CAF, members of the GCN5-related N-acetyltransferase family of histone acetyltransferases, regulate CDK9 function by specifically acetylating the catalytic core of the enzyme and, in particular, a lysine that is essential for ATP coordination and the phosphotransfer reaction. Acetylation markedly reduces both the kinase function and transcriptional activity of P-TEFb. In contrast to unmodified CDK9, the acetylated fraction of the enzyme is specifically found in the insoluble nuclear matrix compartment. Acetylated CDK9 associates with the transcriptionally silent human immunodeficiency virus type 1 provirus; upon transcriptional activation, it is replaced by the unmodified form, which is involved in the elongating phase of transcription marked by Ser2-phosphorylated RNAPII. Given the conservation of the CDK9 acetylated residues in the catalytic task of virtually all CDK proteins, we anticipate that this mechanism of regulation might play a broader role in controlling the function of other members of this kinase family.
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PMID:Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription. 1825 Jan 57

Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is an inhibitor of the positive transcription elongation factor b (P-TEFb), which controls RNA polymerase II transcription and human immunodeficiency virus Tat transactivation. In cells, more than half of P-TEFb is associated with HEXIM1 resulting in the inactivation of P-TEFb. Recently, we found that nucleophosmin (NPM), a key factor involved in p53 signaling pathway, interacts with HEXIM1 and activates P-TEFb-dependent transcription. Here we report that human double minute-2 protein (HDM2), a p53-specific E3 ubiquitin ligase, specifically ubiquitinates HEXIM1 through the lysine residues located within the basic region of HEXIM1. However, the HDM2-induced HEXIM1 ubiquitination does not lead to proteasome-mediated protein degradation. Fusion of ubiquitin to HEXIM1 demonstrates stronger inhibition on P-TEFb-dependent transcription. Our results demonstrate that HDM2 functions as a specific E3 ubiquitin ligase for HEXIM1, suggesting a possible role for HEXIM1 ubiquitination in the regulation of P-TEFb activity.
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PMID:Ubiquitination of HEXIM1 by HDM2. 1968 63

The stalling of RNA polymerase II (RNAPII) at the promoters of many genes, including developmental regulators, stress-responsive genes, and HIVLTR, suggests transcription elongation as a critical regulatory step in addition to initiation. Spt5, the large subunit of the DRB sensitivity-inducing factor (DSIF), represses or activates RNAPII elongation in vitro. How RNAPII elongation is repressed in vivo is not well understood. Here we report that CTR1 and CTR2CT, the two repeat-containing regions constituting the C-terminus of Spt5, play a redundant role in repressing RNAPII elongation in vivo. First, mis-expression of Spt5 lacking CTR1 or CTR2CT is inconsequential, but mis-expression of Spt5 lacking the entire C-terminus (termed NSpt5) dominantly impairs embryogenesis in zebrafish. Second, NSpt5 de-represses the transcription of hsp70-4 in zebrafish embryos and HIVLTR in cultured human cells, which are repressed at the RNAPII elongation step under non-inducible conditions. Third, NSpt5 directly associates with hsp70-4 chromatin in vivo and increases the occupancy of RNAPII, positive transcription elongation factor b (P-TEFb), histone H3 Lys 4 trimethylation (H3K4Me3), and surprisingly, the negative elongation factor A (NELF-A) at the locus, indicating a direct action of NSpt5 on the elongation repressed locus. Together, these results reveal a dominant activity of NSpt5 to de-repress RNAPII elongation, and suggest that the C-terminus of Spt5 is critical for repressing RNAPII elongation in vivo.
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PMID:Repression of RNA polymerase II elongation in vivo is critically dependent on the C-terminus of Spt5. 1974 26

The phosphorylation of the serine 10 at histone H3 has been shown to be important for transcriptional activation. Here, we report the molecular mechanism through which H3S10ph triggers transcript elongation of the FOSL1 gene. Serum stimulation induces the PIM1 kinase to phosphorylate the preacetylated histone H3 at the FOSL1 enhancer. The adaptor protein 14-3-3 binds the phosphorylated nucleosome and recruits the histone acetyltransferase MOF, which triggers the acetylation of histone H4 at lysine 16 (H4K16ac). This histone crosstalk generates the nucleosomal recognition code composed of H3K9acS10ph/H4K16ac determining a nucleosome platform for the bromodomain protein BRD4 binding. The recruitment of the positive transcription elongation factor b (P-TEFb) via BRD4 induces the release of the promoter-proximal paused RNA polymerase II and the increase of its processivity. Thus, the single phosphorylation H3S10ph at the FOSL1 enhancer triggers a cascade of events which activate transcriptional elongation.
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PMID:Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. 1976 66

Cyclin-dependent kinase-9 (CDK9) was originally characterized as a transcription elongation factor which regulates RNA Polymerase II (RNAPII) activity following transcriptional initiation. However, recent evidence from a number of studies have shown that CDK9 plays an important role in regulating not only RNAPII activity but also co-transcriptional histone modification and mRNA processing events such as splicing and 3' end processing. Importantly, our previous work and the work presented here demonstrate that CDK9 functions to guide a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3. This function appears to be dependent upon not only the phosphorylation of the RNA Polymerase II C-terminal domain but also upon other CDK9 targets such as the Suppressor of Ty Homolog-5 (SUPT5H), Negative Elongation Factor-E (NELF-E) and probably the human Rad6 homolog UBE2A. We provide a working model by which CDK9 may control co-transcriptional replication-dependent histone mRNA 3' end processing in an H2Bub1 and H3K4me3-dependent manner and uncover new and important differences between the functions of human CDK9 and its yeast counterparts Ctk1 and Bur1.
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PMID:Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing. 1984 66

Spt4-Spt5, a general transcription elongation factor for RNA polymerase II, also has roles in chromatin regulation. However, the relationships between these functions are not clear. Previously, we isolated suppressors of a Saccharomyces cerevisiae spt5 mutation in genes encoding members of the Paf1 complex, which regulates several cotranscriptional histone modifications, and Chd1, a chromatin remodeling enzyme. Here, we show that this suppression of spt5 can result from loss of histone H3 lysines 4 or 36 methylation, or reduced recruitment of Chd1 or the Rpd3S complex. These spt5 suppressors also rescue the synthetic growth defects observed in spt5 mutants that also lack elongation factor TFIIS. Using a FLO8 reporter gene, we found that a chd1 mutation caused cryptic initiation of transcription. We further observed enhancement of cryptic initiation in chd1 isw1 mutants and increased histone acetylation in a chd1 mutant. We suggest that, as previously proposed for H3 lysine 36 methylation and the Rpd3S complex, H3 lysine 4 methylation and Chd1 function to maintain normal chromatin structures over transcribed genes, and that one function of Spt4-Spt5 is to help RNA polymerase II overcome the repressive effects of these histone modifications and chromatin regulators on transcription.
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PMID:Histone H3K4 and K36 methylation, Chd1 and Rpd3S oppose the functions of Saccharomyces cerevisiae Spt4-Spt5 in transcription. 1994 87

The Tat protein of HIV-1 plays an essential role in HIV gene expression by promoting efficient elongation of viral transcripts. Posttranslational modifications of Tat fine-tune interactions of Tat with cellular cofactors and TAR RNA, a stem-loop structure at the 5' ends of viral transcripts. Here, we identify the lysine methyltransferase Set7/9 (KMT7) as a coactivator of HIV transcription. Set7/9-KMT7 associates with the HIV promoter in vivo and monomethylates lysine 51, a highly conserved residue located in the RNA-binding domain of Tat. Knockdown of Set7/9-KMT7 suppresses Tat transactivation of the HIV promoter, but does not affect the transcriptional activity of methylation-deficient Tat (K51A). Set7/9-KMT7 binds TAR RNA by itself and in complex with Tat and the positive transcription elongation factor P-TEFb. Our findings uncover a positive role for Set7/9-KMT7 and Tat methylation during early steps of the Tat transactivation cycle.
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PMID:The Cellular lysine methyltransferase Set7/9-KMT7 binds HIV-1 TAR RNA, monomethylates the viral transactivator Tat, and enhances HIV transcription. 2022 60

Bromodomain-containing protein 4 (Brd4) contains two tandem bromodomains (BD1 and BD2) that bind preferentially to acetylated lysine residues found in histones and nonhistone proteins. This molecular recognition allows Brd4 to associate with acetylated chromatin throughout the cell cycle and regulates transcription at targeted loci. Recruitment of positive transcription elongation factor b, and possibly the general initiation cofactor Mediator as well, plays an important role in Brd4-regulated transcription. Selective contacts with acetyl-lysines in nucleosomal histones and chromatin-binding factors likely provide a molecular switch modulating the steps from chromatin targeting to transcriptional regulation, thus further expanding the 'acetylation code' for combinatorial regulation in eukaryotes.
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PMID:Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4. 2049 83

Transcription-coupled repair (TCR) and global genomic repair (GGR) are two pathways of nucleotide excision repair (NER). In Saccharomyces cerevisiae, Rad26 is important but not absolutely required for TCR. Rpb4, a nonessential RNA polymerase II (Pol II) subunit that forms a subcomplex with Rpb7, and the Spt4-Spt5 complex, a transcription elongation factor, have been shown to suppress Rad26-independent TCR. The Pol II-associated factor 1 complex (Paf1C) has been shown to function in transcription elongation, 3'-processing of mRNAs, and posttranslational modification of histones. Here we show that Paf1C plays a marginal role in facilitating Rad26-dependent TCR but significantly suppresses Rad26-independent TCR. The suppression of Rad26-independent TCR is achieved by cooperating with Spt4-Spt5. We propose a model that, in the absence of Rad26, a lesion is "locked" in the active center of a Pol II elongation complex, which is stabilized by the coordinated interactions of Rpb4-Rpb7, Spt4-Spt5, and Paf1C with each other and with the core Pol II. We also found that Paf1C facilitates GGR, especially in internucleosomal linker regions. The facilitation of GGR is achieved through enabling monoubiquitination of histone H2B lysine 123 by Bre1, which in turn permits di- and trimethylation of histone H3 lysine 79 by Dot1. To our best knowledge, among the NER-modulating factors documented so far, Paf1C appears to have the most diverse functions in different NER pathways or subpathways.
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PMID:Diverse roles of RNA polymerase II-associated factor 1 complex in different subpathways of nucleotide excision repair. 2173 40


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