Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nucleolin is a major nucleolar protein conserved in all eukaryotic organisms. It is a multifunctional protein involved in different cellular aspects like chromatin organization and stability, DNA and RNA metabolism, assembly of ribonucleoprotein complexes, cytokinesis, cell proliferation and stress response. The multifunctionality of nucleolin is linked to its tripartite structure, post-translational modifications and its ability of shuttling from and to the nucleolus/nucleoplasm and cytoplasm. Nucleolin has been now studied for many years and its activities and properties have been described in a number of excellent reviews. Here, we overview the role of nucleolin in RNA polymerase I (RNAPI) transcription and describe recent results concerning its functional interaction with rDNA chromatin organization. For a long time, nucleolin has been associated with rRNA gene expression and pre-rRNA processing. However, the functional connection between nucleolin and active versus inactive rRNA genes is still not fully understood. Novel evidence indicates that the nucleolin protein might be required for controlling the transcriptional ON/OFF states of rDNA chromatin in both mammals and plants.
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PMID:Nucleolin: dual roles in rDNA chromatin transcription. 2522 27

Various cellular stresses activate autophagy, which is involved in lysosomal degradation of cytoplasmic materials for maintaining nutrient homeostasis and eliminating harmful components. Here, we show that RNA polymerase I (Pol I) transcription inhibition induces nucleolar disruption and autophagy. Treatment with autophagy inhibitors or siRNA specific for autophagy-related (ATG) proteins inhibited autophagy but not nucleolar disruption induced by Pol I transcription inhibition, which suggested that nucleolar disruption was upstream of autophagy. Furthermore, treatment with siRNA specific for nucleolar protein nucleophosmin (NPM) inhibited this type of autophagy. This showed that NPM was involved in autophagy when the nucleolus was disrupted by Pol I inhibition. In contrast, NPM was not required for canonical autophagy induced by nutrient starvation, as it was not accompanied by nucleolar disruption. Thus, our results revealed that, in addition to canonical autophagy, there may be NPM-dependent autophagy associated with nucleolar disruption.
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PMID:The nucleolar protein nucleophosmin is essential for autophagy induced by inhibiting Pol I transcription. 2575 92

DDX11 was recently identified as a cause of Warsaw breakage syndrome (WABS). However, the functional mechanism of DDX11 and the contribution of clinically described mutations to the pathogenesis of WABS are elusive. Here, we show that DDX11 is a novel nucleolar protein that preferentially binds to hypomethylated active ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF) and the RNA polymerase I (Pol I). DDX11 knockdown changed the epigenetic state of rDNA loci from euchromatic structures to more heterochromatic structures, reduced the activity of UBF, decreased the recruitment of UBF and RPA194 (a subunit of Pol I) to rDNA promoter, suppressed rRNA transcription and thereby inhibited growth and proliferation of HeLa cells. Importantly, two indentified WABS-derived mutants, R263Q and K897del, and a Fe-S deletion construct demonstrated significantly reduced binding abilities to rDNA promoters and lowered DNA-dependent ATPase activities compared with wild-type DDX11. Knockdown of the zebrafish ortholog of human DDX11 by morpholinos resulted in growth retardation and vertebral and craniofacial malformations in zebrafish, concomitant with the changes in histone epigenetic modifications at rDNA loci, the reduction of Pol I recruitment to the rDNA promoter and a significant decrease in nascent pre-RNA levels. These growth disruptions in zebrafish in response to DDX11 reduction showed similarities to the clinically described developmental abnormalities found in WABS patients for the first time in any vertebrate. Thus, our results indicate that DDX11 functions as a positive regulator of rRNA transcription and provides a novel insight into the pathogenesis of WABS.
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PMID:The Warsaw breakage syndrome-related protein DDX11 is required for ribosomal RNA synthesis and embryonic development. 2608 3

Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and E2F1 target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy.
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PMID:Nucleolar repression facilitates initiation and maintenance of senescence. 2650 14

The RING finger protein TRAIP protects genome integrity and its mutation causes Seckel syndrome. TRAIP encodes a nucleolar protein that migrates to UV-induced DNA lesions via a direct interaction with the DNA replication clamp PCNA. Thus far, mechanistically how UV mobilizes TRAIP from the nucleoli remains unknown. We found that PCNA binding is dispensable for the nucleolus-nucleoplasm shuttling of TRAIP following cell exposure to UV irradiation, and that its redistribution did not rely on the master DNA damage kinases ATM and ATR. Interestingly, I-PpoI-induced ribosomal DNA damage led to TRAIP exclusion from the nucleoli, raising the possibility that active ribosomal DNA transcription may underlie TRAIP retention in the nuclear sub-compartments. Accordingly, chemical inhibition of RNA polymerase I activity led to TRAIP diffusion into the nucleoplasm, and was coupled with marked reduction of DNA/RNA hybrids in the nucleoli, suggesting that TRAIP may be sequestered via binding to nucleic acid structures in the nucleoli. Consistently, cell pre-treatment with DNase/RNase effectively released TRAIP from the nucleoli. Taken together, our study defines a bipartite mechanism that drives TRAIP trafficking in response to UV damage, and highlights the nucleolus as a stress sensor that contributes to orchestrating DNA damage responses.
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PMID:Nucleolar residence of the seckel syndrome protein TRAIP is coupled to ribosomal DNA transcription. 3016 63

The nucleolus is a membraneless organelle of the nucleus and the site of rRNA synthesis, maturation, and assembly into preribosomal particles. The nucleolus, organized around arrays of rRNA genes (rDNA), dissolves during prophase of mitosis in metazoans, when rDNA transcription ceases, and reforms in telophase, when rDNA transcription resumes. No such dissolution and reformation cycle exists in budding yeast, and the precise course of nucleolar segregation remains unclear. By quantitative live-cell imaging, we observed that the yeast nucleolus is reorganized in its protein composition during mitosis. Daughter cells received equal shares of preinitiation factors, which bind the RNA polymerase I promoter and the rDNA binding barrier protein Fob1, but only about one-third of RNA polymerase I and the processing factors Nop56 and Nsr1. The distribution bias was diminished in nonpolar chromosome segregation events observable in dyn1 mutants. Unequal distribution, however, was enhanced by defects in RNA polymerase I, suggesting that rDNA transcription supports nucleolar segregation. Indeed, quantification of pre-rRNA levels indicated ongoing rDNA transcription in yeast mitosis. These data, together with photobleaching experiments to measure nucleolar protein dynamics in anaphase, consolidate a model that explains the differential partitioning of nucleolar components in budding yeast mitosis.
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PMID:Compositional reorganization of the nucleolus in budding yeast mitosis. 3062 28

Ribosomal RNA (rRNA) production occurs in the nucleolus and is a critical process for ribosome biogenesis which affects protein synthesis capacity and determines the cell growth. Dysregulation of nucleolar homeostasis elicits a nucleolar stress response and is related to disease etiology, indicating that the regulation of nucleolar activity is crucial and tightly coordinated. We previously reported that nucleolar protein pNO40 overexpression mediates SR family splicing factors into the nucleolus and impairs mRNA metabolism, while the function of pNO40 in nucleolar homeostasis is unclear. Here, we demonstrate that overexpression of pNO40 downregulates RNA polymerase I transcription activity, resulting in pre-rRNA synthesis reduction and induces nucleolar segregation, a hallmark of rRNA synthesis inhibition and nucleolar stress response. Moreover, co-immunoprecipitation experiments revealed that ectopically expressed pNO40 interacts with UBF, a master transcription factor involved in pre-initiation complex (PIC) (containing SL-1 complex and RNA polymerase I complex) to activate and promote RNA polymerase I-mediated transcription, but disturbs its rDNA promoter binding ability. Collectively, our results demonstrate the role of pNO40 in rRNA biosynthesis regulation by compromising UBF function in rDNA transcription activation with subsequent rRNA synthesis inhibition.
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PMID:Ectopically expressed pNO40 suppresses ribosomal RNA synthesis by inhibiting UBF-dependent transcription activation. 3121 76

Rta of Epstein-Barr virus (EBV) is thought to be expressed only during the lytic cycle to promote the transcription of lytic genes. However, we found that Rta is expressed in EBV-infected B cells during viral latency, at levels detectable by immunoblot analysis. Latent Rta expression cannot be attributed to spontaneous lytic activation, as we observed that more than 90% of Akata, P3HR1, and 721 cells latently infected by EBV express Rta. We further found that Rta is sequestered in the nucleolus during EBV latency through its interaction with MCRS2, a nucleolar protein. When Rta is sequestered in the nucleolus, it no longer activates RNA polymerase II-driven transcription, thus explaining why Rta expression during latency does not transactivate EBV lytic genes. Additional experiments showed that Rta can bind to 18S rRNA and become incorporated into ribosomes, and a transient transfection experiment showed that Rta promotes translation from an mRNA reporter. These findings reveal that Rta has novel functions beyond transcriptional activation during EBV latency and may have interesting implications for the concept of EBV latency.
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PMID:Expression of Rta in B Lymphocytes during Epstein-Barr Virus Latency. 3271 Sep 85


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