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

---

Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper studies the molecular organization, neuronal distribution and cellular differentiation dynamics of the giant fibrillar centers (GFCs) of nucleoli in rat sensory ganglia neurons. The GFC appeared as a round nucleolar domain (1-2 microm in diameter) partially surrounded by the dense fibrillar component and accompanied by numerous small FCs. By immunocytochemistry, the GFC concentrated the upstream binding factor, which may serve as a marker of this structure, and also contain RNA polymerase I, DNA topoisomerase I, SUMO-1 and Ubc9. However, they lack ubiquitin-proteasome conjugates and 20S proteasome. Transcription assay with 5'-fluorouridine incorporation revealed the presence of nascent RNA on the dense fibrillar component of the neuronal nucleolus, but not within the low electron-density area of the GFC. The formation of GFCs is neuronal size dependent: they were found in 58%, 30% and 0% of the large, medium and small neurons, respectively. GFCs first appeared during the postnatal period, concomitantly with a stage of neuronal growth, myelination and bioelectrical maturation. GFCs were not observed in segregated nucleoli induced by severe inhibition of RNA synthesis. We suggest that the formation of GFCs is associated with a high rate of ribosome biogenesis of the transcriptionally more active large-size neurons.
...
PMID:The giant fibrillar center: a nucleolar structure enriched in upstream binding factor (UBF) that appears in transcriptionally more active sensory ganglia neurons. 1758 96

Expansions of CAG repeat tracts in the germ line underlie several neurological diseases. In human patients and mouse models, CAG repeat tracts display an ongoing instability in neurons, which may exacerbate disease symptoms. It is unclear how repeats are destabilized in nondividing cells, but it cannot involve DNA replication. We showed previously that transcription through CAG repeats induces their instability (Y. Lin, V. Dion, and J. H. Wilson, Nat. Struct. Mol. Biol. 13:179-180). Here, we present a genetic analysis of the link between transcription-induced repeat instability and nucleotide excision repair (NER) in human cells. We show that short interfering RNA-mediated knockdown of CSB, a component specifically required for transcription-coupled NER (TC-NER), and knockdowns of ERCC1 and XPG, which incise DNA adjacent to damage, stabilize CAG repeat tracts. These results suggest that TC-NER is involved in the pathway for transcription-induced CAG repeat instability. In contrast, knockdowns of OGG1 and APEX1, key components involved in base excision repair, did not affect repeat instability. In addition, repeats are stabilized by knockdown of transcription factor IIS, consistent with a requirement for RNA polymerase II (RNAPII) to backtrack from a transcription block. Repeats also are stabilized by knockdown of either BRCA1 or BARD1, which together function as an E3 ligase that can ubiquitinate arrested RNAPII. Treatment with the proteasome inhibitor MG132, which stabilizes repeats, confirms proteasome involvement. We integrate these observations into a tentative pathway for transcription-induced CAG repeat instability that can account for the contractions observed here and potentially for the contractions and expansions seen with human diseases.
...
PMID:Transcription-induced CAG repeat contraction in human cells is mediated in part by transcription-coupled nucleotide excision repair. 1759 97

Che-1 is a RNA polymerase II binding protein involved in the transcriptional regulation of E2F target genes and in cell proliferation. Recently, it has been shown that Che-1 accumulates in cells responding to genotoxic agents such as Doxorubicin and ionizing radiation. The DNA damage-activated checkpoint kinases ATM and Chk2 interact with and phosphorylate Che-1, enhancing its accumulation and stability, and promoting Che-1-mediated transcription of p53-responsive genes and of p53 itself, as evidenced by microarray analysis. This transcriptional response is suppressed by expression of a Che-1 mutant lacking ATM and Chk2 phosphorylation amino acid residues, or by depletion of Che-1 by RNA silencing. In addition, chromatin immunoprecipitation analysis has shown that Che-1 is released from E2F target genes and recruited to the p21 and p53 promoters after DNA damage. Che-1 contributes to the maintenance of the G2/M checkpoint in response to genotoxic stress. These findings identify a new mechanism by which the checkpoint kinases regulate, via the novel effector Che-1, the p53 pathway. Lastly, increasing evidence suggests that Che-1 may be involved in apoptotic signaling in neural tissues. In cortical neurons, Che-1 exhibits anti-apoptotic activity, protecting cells from neuronal damage induced by amyloid beta-peptide. In cerebellar granule neurons, Che-1 interacts with Tau in the cytoplasmic compartment and this interaction is modulated during neuronal apoptosis. Finally, Che-1 directly interacts with the neuronal cell-death inducer "NRAGE" which downregulates endogenous Che-1 by targeting it for proteasome-dependent degradation. These findings identify Che-1 as a novel cytoprotective factor against apoptotic insults and suggest that Che-1 may represent a potential target for therapeutic application.
...
PMID:The anti-apoptotic factor Che-1/AATF links transcriptional regulation, cell cycle control, and DNA damage response. 1763 35

Cellular DNA damage elicits the phosphorylation and ubiquitination of RNA polymerase II (RNAPII), leading to the global repression of transcription. In this report we show that there are at least two different pathways to transcriptional repression, depending on the type of DNA damage. After H2O2 treatment, transcription was rapidly inhibited and rapidly restored. On the other hand, UV irradiation caused a much slower transcriptional inhibition, with a corresponding depletion of unphosphorylated RNAPII. We found that after UV treatment, but not treatment with H2O2, the inhibition of transcription was dependent on both the proteasome and new protein synthesis. In addition, RNAPII activity and ubiquitination were regulated through the phosphorylation of RNAPII by the P-TEFb kinase. These results highlight that multiple cellular pathways exist to globally repress transcriptional processes that might interfere with the repair of DNA damage.
...
PMID:Multiple mechanisms contribute to inhibit transcription in response to DNA damage. 1828 Dec 89

Hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) was identified earlier as an inhibitor of positive transcription elongation factor b (P-TEFb), which is a key transcriptional regulator of RNA polymerase II (Pol II). Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. Here, we identify a nucleolar protein, nucleophosmin (NPM), as a HEXIM1-binding protein. NPM binds to HEXIM1 in vitro and in vivo, and functions as a negative regulator of HEXIM1. Over-expression of NPM leads to proteasome-mediated degradation of HEXIM1, resulting in activation of P-TEFb-dependent transcription. In contrast, an increase in HEXIM1 protein levels and a decrease in transcription are detected when NPM is knocked down. We show that a cytoplasmic mutant of NPM, NPMc+, associates with and sequesters HEXIM1 in the cytoplasm resulting in higher RNA Pol II transcription. Correspondingly, cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. Over-expression of NPM has been detected in tumors of various histological origins and our results may provide a possible molecular mechanism for the proto-oncogenic function of NPM. Furthermore, considering that 35% of AML patients are diagnosed with NPMc+ mutation, our findings suggest that in some cases of AML, RNA Pol II transcription may be disregulated by the malfunction of NPM and the mislocation of HEXIM1.
...
PMID:Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. 1837 77

Transcription-coupled repair (TCR) plays a key role in the repair of DNA lesions induced by bulky adducts and is initiated when the elongating RNA polymerase II (Pol II) stalls at DNA lesions. This is accompanied by alterations in Pol II activity and stability. We have previously shown that the monofunctional adducts formed by irofulven (6-hydroxymethylacylfulvene) are exclusively recognized by TCR, without involvement of global genome repair (GGR), making irofulven a unique tool to characterize TCR-associated processes in vivo. Here, we characterize the influence of irofulven on Pol II activity, stability and mobility in living mammalian cells. Our results demonstrate that irofulven induces specific inhibition of nucleoplasmic RNA synthesis, an important decrease of Pol II mobility, coupled to the accumulation of initiating polymerase and a time-dependent loss of the engaged enzyme, associated with its polyubiquitylation. Both proteasome-mediated degradation of the stalled polymerase and new protein synthesis are necessary to allow Pol II recycling into preinitiating complexes. Together, our findings provide novel insights into the subsequent fate of the stalled RNA polymerase II and demonstrate the essential role of the recycling process for transcriptional reinitiation and viability of mammalian cells.
...
PMID:Influence of irofulven, a transcription-coupled repair-specific antitumor agent, on RNA polymerase activity, stability and dynamics in living mammalian cells. 1838 15

The final outcome of protein polyubiquitylation is often proteasome-mediated proteolysis, meaning that "proofreading" of ubiquitylation by ubiquitin proteases (UBPs) is crucial. Transcriptional arrest can trigger ubiquitin-mediated proteolysis of RNA polymerase II (RNAPII) so a UBP reversing RNAPII ubiquitylation might be expected. Here, we show that Ubp3 deubiquitylates RNAPII in yeast. Genetic characterization of ubp3 cells is consistent with a role in elongation, and Ubp3 can be purified with RNAPII, Def1, and the elongation factors Spt5 and TFIIF. This Ubp3 complex deubiquitylates both mono- and polyubiquitylated RNAPII in vitro, and ubp3 cells have elevated levels of ubiquitylated RNAPII in vivo. Moreover, RNAPII is degraded faster in a ubp3 mutant after UV irradiation. Problems posed by damage-arrested RNAPII are thought to be resolved either by removing the damage or degrading the polymerase. In agreement with this, cells with compromised DNA repair are better equipped to survive UV damage when UPB3 is deleted.
...
PMID:Reversal of RNA polymerase II ubiquitylation by the ubiquitin protease Ubp3. 1849 51

Genetic analysis of the Drosophila leg-arista-wing complex (lawc) gene suggests a role for the Lawc protein in chromatin-related processes based on its classification as a trxG gene but the molecular mechanisms of its function remain elusive. We have found that Lawc is a small, cysteine-rich protein that is present in most of the interbands of polytene chromosomes. In agreement with this observation, Lawc co-localizes with RNA polymerase IIo (Pol IIo) and it is recruited to transcribed loci after elongation by Pol IIo has begun. Lawc interacts with the nuclear proteasome regulator dREGgamma in a yeast two-hybrid assay and both proteins co-localize on polytene chromosomes. In addition, a mutation in lawc interacts genetically with a mutation in a component of the proteasome. lawc mutants show decreased expression of some genes, while the levels of Pol IIoSer2 increase. We conclude that Lawc is required for proper transcription by RNA polymerase II in a process that involves the nuclear proteasome.
...
PMID:The Lawc protein is required for proper transcription by RNA polymerase II in Drosophila. 1871 97

Significant amount of data have accumulated in the last several years pointing to the essential role of the ubiquitin proteasome system in the regulation of RNA polymerase II transcription; however, its involvement in RNA polymerase I transcription has remained largely unexplored. In this study, we demonstrate that proteasome activity is required for pre-rRNA synthesis. We can detect the association of proteasomal ATPases with both the rDNA promoter and coding region. Additionally, we show that the RNA polymerase I associated transcription factor, TIF-IA interacts with proteasomal ATPases, representing a potential link via which proteasomes and/or proteasome related complexes are recruited to rRNA genes. In summary, our findings suggest that the ubiquitin proteasome system is directly involved in RNA polymerase I transcription in analogy to the RNA polymerase II system.
...
PMID:Proteasomal ATPases are associated with rDNA: the ubiquitin proteasome system plays a direct role in RNA polymerase I transcription. 1880 59

The tumor suppressor p53 is activated in response to many forms of cellular stress leading to cell cycle arrest, senescence or apoptosis. Appropriate sub-cellular localization is essential for modulating p53 function. We recently showed that p53 localizes to the nucleolus after proteasome inhibition with MG132 and this localization requires sequences within its carboxyl terminus. In the present study, we found that after treatment with MG132, p53 associates with a discrete sub-nucleolar component, the fibrillar center (FC), a region mainly enriched with RNA polymerase I. Moreover, we now demonstrate that this localization is an energy-dependent process as reduction of ATP levels prevents nucleolar localization. In addition, p53 sub-nucleolar accumulation is abolished when cells are subjected to various types of genotoxic stress. Furthermore, we show that monoubiquitination of p53, which causes it to localize to the cytoplasm and nucleoplasm, does not prevent the association of p53 with the nucleolus after MG132 treatment. Importantly, we demonstrate that p53 nucleolar association occurs in lung and bladder carcinomas.
...
PMID:p53 is localized to a sub-nucleolar compartment after proteasomal inhibition in an energy-dependent manner. 1903 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---