The Timing of Ribosomal RNA Modification During Eukaryotic Ribosome Biogenesis
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PROVIDER: PRJEB93886 | ENA |
REPOSITORIES: ENA
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Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
2020-09-14 | GSE137951 | GEO
Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
2020-09-14 | GSE157208 | GEO
Project description:The budding yeast E3 SUMO ligase Mms21, a component of the Smc5-6 complex, regulates sister chromatid cohesion, DNA replication, and DNA repair. We identify a role for Mms21 in ribosome biogenesis. The mms21RINGD mutant exhibits reduced rRNA production, nuclear accumulation of 60S and 40S ribosomal proteins, and elevated Gcn4 translation. Genes involved in ribosome biogenesis and translation are down-regulated in the mms21RINGD mutant. Examining gene expression profile of mms21RINGD mutant compared to wild-type by RNA Seq using Ilumina sequencing
2015-06-13 | E-GEOD-69826 | biostudies-arrayexpress
Project description:Early eukaryotic ribosome biogenesis involves large multi-protein complexes, which co-transcriptionally associate with pre-ribosomal RNA to form the small subunit processome. The precise mechanisms by which two of the largest multi-protein complexes – UtpA and UtpB – interact with nascent pre-ribosomal RNA have so far been poorly understood. We have combined biochemical and structural biology approaches with ensembles of RNA-protein cross-linking to elucidate the essential function of both complexes. Here we show that UtpA contains a large composite RNA binding site and captures the 5´ end of pre-ribosomal RNA. UtpB forms an extended structure that binds early pre-ribosomal intermediates in close proximity to key architectural sites such as an RNA duplex formed by the 5´ ETS and U3 snoRNA as well as the 3´ boundary of 18S rRNA. Both complexes therefore act as vital RNA chaperones to initiate eukaryotic ribosome assembly.
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Project description:The budding yeast E3 SUMO ligase Mms21, a component of the Smc5-6 complex, regulates sister chromatid cohesion, DNA replication, and DNA repair. We identify a role for Mms21 in ribosome biogenesis. The mms21RINGD mutant exhibits reduced rRNA production, nuclear accumulation of 60S and 40S ribosomal proteins, and elevated Gcn4 translation. Genes involved in ribosome biogenesis and translation are down-regulated in the mms21RINGD mutant.
2015-06-13 | GSE69826 | GEO
Project description:In all domains of life, the rate of protein synthesis is directly linked to the rates of cell growth and proliferation. Consequently, highly proliferative cancer cells are especially sensitive to perturbations in ribosome biogenesis. While ribosome synthesis and cancer have a well-established relationship, only recently has ribosome biogenesis drawn interest as a cancer therapeutic target. Here, we have exploited the relationship between ribosome biogenesis and cancer cell proliferation by using a potent ribosome biogenesis inhibitor: RBI2 (Ribosome Biogenesis Inhibitor 2) to perturb cancer cell growth and viability. We demonstrate that RBI2 significantly decreases cell viability in malignant melanoma cells and breast cancer cell lines. Treatment with RBI2 dramatically and rapidly decreases ribosomal RNA (rRNA) synthesis, without affecting the occupancy of RNA polymerase I (Pol I) on the ribosomal DNA template. Next-generation RNA sequencing (RNA-seq) reveals that RBI2 and previously described ribosome biogenesis inhibitor CX-5461 induce distinct changes in the transcriptome. Investigation of the content of the pre-rRNAs through RT-qPCR reveals an increase in polyadenylation of cellular rRNA after treatment with RBI2, a known pathway by which rRNA degradation occurs. Northern blotting revealed that RBI2 does not appear to impair or alter rRNA processing. Collectively, these data suggest that RBI2 inhibits rRNA synthesis distinctly from other previously described ribosome biogenesis inhibitors, potentially through a novel pathway that upregulates turnover of premature rRNAs.
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Project description:We simultaneously characterized alterations of both ribosome quality and quantity in high grade adult-type diffuse glioma. Unexpectedly, we uncovered that glioblastomas display the most prominent defects in ribosomal RNA chemical modifications (quality) while astrocytomas and oligodendrogliomas rather exhibit changes in ribosome biogenesis (quantity). Moreover, glioma cell lines exhibit distinct responses to clinically evaluated RNA Pol I inhibitors, CX5461 and BMH-21. This study highlights theranostic opportunities provided by the ribosome field to improve the management of glioma patients.
2023-08-31 | GSE224104 | GEO
Project description:A genome-wide CRISPR/Cas9 knockout reporter screen was performed to identify transcriptional regulators of ribosomal biogenesis genes and ribosomal protein genes. The murine GeCKO v2 library provided by the Zhang lab was amplified and positive control sgRNAs targeting the reporters were spiked-in. NIH/3T3 cells (murine fibroblasts) harboring the "ribosome biogenesis" reporter Fbl-GFP (Fibrillarin promoter-driven enhanced GFP fused to the PEST domain of the murine ornithine decarboxylase) and the "ribosomal protein" reporter Rpl18-RFP (Rpl18 promoter-driven TurboRFP fused to the PEST domain of the murine ornithine decarboxylase) were transduced with the aforementioned library, selected and FACS-sorted six days after infection. The sorted conditions were i) low GFP, but middle to strong RFP expression (RiBi down); ii) low RFP, but middle to strong GFP expression (RP down); iii) low GFP and low RFP expression (Both down); iv) strong GFP and strong RFP expression (Both up). The same amount of cells that were used for sorting, were harvested as the "unsorted" condition to which all sorted samples were compared to. The plasmid library was also sequenced.
2022-07-13 | GSE207900 | GEO
Project description:The rapid transport of ribosomal proteins (RPs) into the nucleus and their efficient assembly into rRNA are prerequisites for ribosome biogenesis. Proteins that act as dedicated chaperones for RPs to maintain their stability and facilitate their assembly have not been identified in filamentous fungi. PlCYP5 is a nuclear cyclophilin in the nematophagous fungus Purpureocillium lilacinum, and up-regulated expression in response to abiotic stress and nematode egg-parasitism. Here, we found that PlCYP5 interacted with the unassembled small ribosomal subunit protein, PlRPS15, of the uS19 family. PlRPS15 contained a eukaryote-specific N-terminal extension that mediated the interaction. The phenotypes of the PlCYP5 loss-of-function mutant were similar to those of the PlRPS15 knockdown mutant (e.g., growth and ribosome biogenesis defects). PlCYP5 maintained the solubility of PlRPS15 independent of its catalytic peptide-prolyl isomerase function and supported the integration of PlRPS15 into pre-ribosomes. PlCYP5 homologs in Arabidopsis thaliana, Homo sapiens, Schizosaccharomyces pombe, Sclerotinia sclerotiorum, Botytis cinerea, and Metarhizium anisopliae were identified. Notably, the interaction of their homologs corresponding to the PlCYP5-PlRPS15 pattern existed in three filamentous fungi, while lacked in other species. In summary, our data disclosed a special RP dedicated chaperone system in filamentous fungi, in which cyclophilin was enlisted to perform the chaperone funtion.
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