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:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rpb9, a nonessential subunit of RNA polymerase II (Pol II), has multiple transcription-related functions in Saccharomyces cerevisiae, including transcription elongation and transcription-coupled repair (TCR). Here we show that, in response to UV radiation, Rpb9 also functions in promoting ubiquitylation and degradation of Rpb1, the largest subunit of Pol II. This function of Rpb9 is not affected by any pathways of nucleotide excision repair, including TCR mediated by Rpb9 itself and by Rad26. Rpb9 is composed of three distinct domains: the N-terminal Zn1, the C-terminal Zn2, and the central linker. The Zn2 domain, which is dispensable for transcription elongation and TCR functions, is essential for Rpb9 to promote Rpb1 degradation, whereas the Zn1 and linker domains, which are essential for transcription elongation and TCR functions, play a subsidiary role in Rpb1 degradation. Coimmunoprecipitation analysis suggests that almost the full length of Rpb9 is required for a strong interaction with the core Pol II: deletion of the Zn2 domain causes dramatically weakened interaction, whereas deletion of Zn1 and the linker resulted in undetectable interaction. Furthermore, we show that Rpb1, rather than the whole Pol II complex, is degraded in response to UV radiation and that the degradation is primarily mediated by the 26S proteasome.
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PMID:Yeast Rpb9 plays an important role in ubiquitylation and degradation of Rpb1 in response to UV-induced DNA damage. 1745 55

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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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PMID:Proteasomal ATPases are associated with rDNA: the ubiquitin proteasome system plays a direct role in RNA polymerase I transcription. 1880 59

Emerging evidence suggests that components of the ubiquitin-proteasome system are involved in the regulation of gene expression. A variety of factors, including transcriptional activators, coactivators, and histones, are controlled by ubiquitylation, but the mechanisms through which this modification can function in transcription are generally unknown. Here, we report that the Saccharomyces cerevisiae protein Asr1 is a RING finger ubiquitin-ligase that binds directly to RNA polymerase II via the carboxyl-terminal domain (CTD) of the largest subunit of the enzyme. We show that interaction of Asr1 with the CTD depends on serine-5 phosphorylation within the CTD and results in ubiquitylation of at least 2 subunits of the enzyme, Rpb1 and Rpb2. Ubiquitylation by Asr1 leads to the ejection of the Rpb4/Rpb7 heterodimer from the polymerase complex and is associated with inactivation of polymerase function. Our data demonstrate that ubiquitylation can directly alter the subunit composition of a core component of the transcriptional machinery and provide a paradigm for how ubiquitin can influence gene activity.
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PMID:Modulation of RNA polymerase II subunit composition by ubiquitylation. 1906 26


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