scholarly journals Signal Transduction in Ribosome Biogenesis: A Recipe to Avoid Disaster

2019 ◽  
Vol 20 (11) ◽  
pp. 2718 ◽  
Author(s):  
Manuela Piazzi ◽  
Alberto Bavelloni ◽  
Angela Gallo ◽  
Irene Faenza ◽  
William L. Blalock
Keyword(s):  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Protein Translation ◽  
Rrna Synthesis ◽  
Environmental Cues ◽  
Surface Receptors ◽  
Cellular Events ◽  
Eif2α Kinase ◽  
Amino Acid Depletion ◽  
Stress Oxidative

Energetically speaking, ribosome biogenesis is by far the most costly process of the cell and, therefore, must be highly regulated in order to avoid unnecessary energy expenditure. Not only must ribosomal RNA (rRNA) synthesis, ribosomal protein (RP) transcription, translation, and nuclear import, as well as ribosome assembly, be tightly controlled, these events must be coordinated with other cellular events, such as cell division and differentiation. In addition, ribosome biogenesis must respond rapidly to environmental cues mediated by internal and cell surface receptors, or stress (oxidative stress, DNA damage, amino acid depletion, etc.). This review examines some of the well-studied pathways known to control ribosome biogenesis (PI3K-AKT-mTOR, RB-p53, MYC) and how they may interact with some of the less well studied pathways (eIF2α kinase and RNA editing/splicing) in higher eukaryotes to regulate ribosome biogenesis, assembly, and protein translation in a dynamic manner.

scholarly journals Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development

2021 ◽  
Author(s):  
Karla Terrazas Falcon ◽  
Kristin Watt ◽  
Soma Dash ◽  
Annita Achilleos ◽  
Emma Moore ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Protein Translation ◽  
Craniofacial Development ◽  
Rrna Synthesis ◽  
Craniofacial Anomalies ◽  
Congenital Diseases ◽  
Tissue Specific ◽  
Rrna Transcription ◽  
Pol I

Ribosomal RNA (rRNA) transcription by RNA Polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies which frequently affect craniofacial development. Here, we present a cellular and molecular mechanism to explain the susceptibility of craniofacial development to disruptions in Pol I transcription. We show that Pol I subunits are highly expressed in the neuroepithelium and neural crest cells (NCC), which generate most of the craniofacial skeleton. High expression of Pol I subunits sustains elevated rRNA transcription in NCC progenitors, which supports their high tissue-specific levels of protein translation, but also makes NCC particulalry sensitive to rRNA synthesis defects. Underpinning these findings, NCC-specific deletion of Pol I subunits Polr1a, Polr1c, and associated factor Tcof1 in mice cell-autonomously diminishes rRNA synthesis, which causes an imbalance between rRNA and ribosomal proteins. This leads to increased ribosomal protein binding to Mdm2 and concomitantly diminished Mdm2 binding to p53. Consequently, p53 protein accumulates, resulting in NCC apoptosis and craniofacial anomalies. Furthermore, compound mutations in Pol I subunits and associated factors specifically exacerbates the craniofacial anomalies characteristic of the ribosomopathies Treacher Collins Syndrome and Acrofacial Dysostosis Cincinnati Type. Our novel results therefore demonstrate the dynamic spatiotemporal requirement for rRNA transcription during mammalian cranial NCC development and corresponding tissue-specific threshold sensitivities to disruptions in rRNA transcription in the pathogenesis of craniofacial congenital diseases.

scholarly journals Che-1/AATF binds to RNA polymerase I machinery and sustains ribosomal RNA gene transcription

2020 ◽  
Vol 48 (11) ◽  
pp. 5891-5906 ◽  
Author(s):  
Cristina Sorino ◽  
Valeria Catena ◽  
Tiziana Bruno ◽  
Francesca De Nicola ◽  
Stefano Scalera ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Cellular Proliferation ◽  
Rna Polymerase I ◽  
Rrna Synthesis ◽  
Rrna Gene ◽  
Response To Stress ◽  
Polymerase I

Abstract Originally identified as an RNA polymerase II interactor, Che-1/AATF (Che-1) has now been recognized as a multifunctional protein involved in cell-cycle regulation and cancer progression, as well as apoptosis inhibition and response to stress. This protein displays a peculiar nucleolar localization and it has recently been implicated in pre-rRNA processing and ribosome biogenesis. Here, we report the identification of a novel function of Che-1 in the regulation of ribosomal RNA (rRNA) synthesis, in both cancer and normal cells. We demonstrate that Che-1 interacts with RNA polymerase I and nucleolar upstream binding factor (UBF) and promotes RNA polymerase I-dependent transcription. Furthermore, this protein binds to the rRNA gene (rDNA) promoter and modulates its epigenetic state by contrasting the recruitment of HDAC1. Che-1 downregulation affects RNA polymerase I and UBF recruitment on rDNA and leads to reducing rDNA promoter activity and 47S pre-rRNA production. Interestingly, Che-1 depletion induces abnormal nucleolar morphology associated with re-distribution of nucleolar proteins. Finally, we show that upon DNA damage Che-1 re-localizes from rDNA to TP53 gene promoter to induce cell-cycle arrest. This previously uncharacterized function of Che-1 confirms the important role of this protein in the regulation of ribosome biogenesis, cellular proliferation and response to stress.

Dynamics and thermal sensitivity of ribosomal RNA maturation paths in plants

2021 ◽  
Author(s):  
Thiruvenkadam Shanmugam ◽  
Deniz Streit ◽  
Frank Schroll ◽  
Jelena Kovacevic ◽  
Enrico Schleiff
Keyword(s):  
High Temperature ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Thermal Sensitivity ◽  
Normal Growth ◽  
Growth Conditions ◽  
High Temperature Stress ◽  
High Temperature Treatment ◽  
Rrna Synthesis ◽  
Rrna Maturation

Abstract Ribosome biogenesis is a constitutive fundamental process for cellular function. Its rate of production depends on the rate of maturation of precursor ribosomal RNA (pre-rRNA). The rRNA maturation paths are marked by four dominant rate-limiting intermediates with cell-type variation of the processivity rate. We have identified that high temperature stress in plants, while halting the existing pre-rRNA maturation schemes, also transiently triggers an atypical pathway for 35S pre-rRNA processing. This pathway leads to production of an aberrant precursor rRNA, reminiscent of yeast 24S, encompassing 18S and 5.8S rRNA that do not normally co-occur together at sub-unit levels; this response is elicited specifically by high and not low temperatures. We show this response to be conserved in two other model crop plant species (Rice and Tomato). This pathway persists even after returning to normal growth conditions for 1 hour and is reset between 1-6 hours after stress treatment, likely, due to resumption of normal 35S pre-rRNA synthesis and processing. The heat-induced ITS2 cleavage-derived precursors and stalled P-A2-like precursors were heterogeneous in nature with a fraction containing polymeric (A) tails. Furthermore, high temperature treatment and subsequent fractionation resulted in polysome and precursor rRNA depletion.

scholarly journals Phosphorylation of Eukaryotic Translation Initiation Factor 2α Coordinates rRNA Transcription and Translation Inhibition during Endoplasmic Reticulum Stress

2009 ◽  
Vol 29 (15) ◽  
pp. 4295-4307 ◽  
Author(s):  
Jenny B. DuRose ◽  
Donalyn Scheuner ◽  
Randal J. Kaufman ◽  
Lawrence I. Rothblum ◽  
Maho Niwa
Keyword(s):  
Endoplasmic Reticulum ◽  
Ribosome Biogenesis ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rrna Synthesis ◽  
Cell Physiology ◽  
Rrna Transcription

ABSTRACT The endoplasmic reticulum (ER) is the major cellular compartment where folding and maturation of secretory and membrane proteins take place. When protein folding needs exceed the capacity of the ER, the unfolded protein response (UPR) pathway modulates gene expression and downregulates protein translation to restore homeostasis. Here, we report that the UPR downregulates the synthesis of rRNA by inactivation of the RNA polymerase I basal transcription factor RRN3/TIF-IA. Inhibition of rRNA synthesis does not appear to involve the well-characterized mTOR (mammalian target of rapamycin) pathway; instead, PERK-dependent phosphorylation of eIF2α plays a critical role in the inactivation of RRN3/TIF-IA. Downregulation of rRNA transcription occurs simultaneously or slightly prior to eIF2α phosphorylation-induced translation repression. Since rRNA is the most abundant RNA species, constituting ∼90% of total cellular RNA, its downregulation exerts a significant impact on cell physiology. Our study demonstrates the first link between regulation of translation and rRNA synthesis with phosphorylation of eIF2α, suggesting that this pathway may be broadly utilized by stresses that activate eIF2α kinases in order to coordinately regulate translation and ribosome biogenesis during cellular stress.

scholarly journals Rrb1p, a Yeast Nuclear WD-Repeat Protein Involved in the Regulation of Ribosome Biosynthesis

2001 ◽  
Vol 21 (4) ◽  
pp. 1260-1271 ◽  
Author(s):  
Tatiana L. Iouk ◽  
John D. Aitchison ◽  
Shawna Maguire ◽  
Richard W. Wozniak
Keyword(s):  
Transcriptional Regulation ◽  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Protein Translation ◽  
Environmental Cues ◽  
Ribosomal Subunits ◽  
Nuclear Extracts ◽  
Coordinated Expression ◽  
Wd Repeat ◽  
Ribosome Biosynthesis

ABSTRACT Ribosome biogenesis is regulated by environmental cues that coordinately modulate the synthesis of ribosomal components and their assembly into functional subunits. We have identified an essential yeast WD-repeat-containing protein, termed Rrb1p, that has a role in both the assembly of the 60S ribosomal subunits and the transcriptional regulation of ribosomal protein (RP) genes. Rrb1p is located in the nucleus and is concentrated in the nucleolus. Its presence is required to maintain normal cellular levels of 60S subunits, 80S ribosomes, and polyribosomes. The function of Rrb1p in ribosome biogenesis appears to be linked to its association with the ribosomal protein rpL3. Immunoprecipitation of Rrb1p from nuclear extracts revealed that it physically interacts with rpL3. Moreover, the overproduction of Rrb1p led to increases in cellular levels of free rpL3 that accumulated in the nucleus together with Rrb1p. The concentration of these proteins within the nucleus was dependent on ongoing protein translation. We also showed that overexpression of RRB1 led to an increase in the expression of RPL3 while all other examined RP genes were unaffected. In contrast, depletion of RRB1 caused an increase in the expression of all RP genes examined except RPL3. These results suggest that Rrb1p regulates RPL3 expression and uncouples it from the coordinated expression of other RP genes.

scholarly journals ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice

Oncogene ◽  
2021 ◽  
Author(s):  
Shiyan Wang ◽  
Chi Chun Wong ◽  
Yanquan Zhang ◽  
Junzhe Huang ◽  
Chuangen Li ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Ribosome Biogenesis ◽  
Zinc Finger Protein ◽  
Transcriptional Repressor ◽  
Protein Translation ◽  
Rrna Synthesis ◽  
Synthesis Inhibitor ◽  
Colorectal Tumorigenesis ◽  
Normal Tissues ◽  
Rrna Transcription

AbstractRibosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation. We investigate the functional and molecular mechanism of Zinc finger protein 545 (ZNF545), a transcriptional repressor for ribosomal RNA (rRNA), in colorectal cancer (CRC). ZNF545 was silenced in CRC compared to adjacent normal tissues (P < 0.0001), implying a tumor-suppressive role. Colon-specific Znf545 knockout in mice accelerated CRC in ApcMin/+ and azoxymethane/dextran sulfate sodium-induced CRC. Mechanistically, we demonstrated that ZNF545 uses its two zinc finger clusters to bind to minimal rDNA promoter, where it assembled transcriptional repressor complex by interacting with KAP1. Znf545 deletion in mouse embryonic fibroblasts not only increased rRNA transcription rate and the nucleolar size and number but also altered the nucleolar composition and architecture with an increased number of fibrillar centers surrounded by net-like dense fibrillar components. Consequently, Znf545 deletion promoted the gene expression of translation machinery, protein translation, and cell growth. Consistent with its tumor-suppressive role, ZNF545 overexpression in CRC cells induced growth arrest and apoptosis. Finally, administration of rRNA synthesis inhibitor, CX-5461, inhibited CRC development in Znf545Δ/ΔApcMin/+ mice. In conclusion, ZNF545 suppresses CRC through repressing rRNA transcription and protein translation. Targeting rRNA biosynthesis in ZNF545-silenced tumors is a potential therapeutic strategy for CRC.

scholarly journals How Cancer Exploits Ribosomal RNA Biogenesis: A Journey beyond the Boundaries of rRNA Transcription

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1098 ◽  
Author(s):  
Gaviraghi ◽  
Vivori ◽  
Tonon
Keyword(s):  
Growth Rate ◽  
Cancer Cells ◽  
Ribosomal Rna ◽  
Tumor Suppressors ◽  
Ribosome Biogenesis ◽  
Regulatory Networks ◽  
Protein Translation ◽  
Rna Transcription ◽  
Rrna Transcription ◽  
Rna Biogenesis

The generation of new ribosomes is a coordinated process essential to sustain cell growth. As such, it is tightly regulated according to cell needs. As cancer cells require intense protein translation to ensure their enhanced growth rate, they exploit various mechanisms to boost ribosome biogenesis. In this review, we will summarize how oncogenes and tumor suppressors modulate the biosynthesis of the RNA component of ribosomes, starting from the description of well-characterized pathways that converge on ribosomal RNA transcription while including novel insights that reveal unexpected regulatory networks hacked by cancer cells to unleash ribosome production.

scholarly journals Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors

2021 ◽  
Author(s):  
Melvin Pan ◽  
Christiane Zorbas ◽  
Maki Sugaya ◽  
Kensuke Ishiguro ◽  
Miki Kato ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Elongation Factor ◽  
Rrna Synthesis ◽  
Nutrient Deprivation ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Sequential Assembly

SummaryRibosome biogenesis involves the processing of precursor ribosomal RNAs (pre-rRNAs) and sequential assembly with ribosomal proteins. Here we report that nutrient deprivation severely impairs pre-rRNA processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, the accumulated pre-rRNAs are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient deprivation leads to perturbed ribosome assembly during nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine was dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which was in turn dependent on Raf/MEK/ERK signalling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that cancer cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

scholarly journals DNA Intercalators Inhibit Eukaryotic Ribosomal RNA Synthesis by Impairing the Initiation of Transcription

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1412
Author(s):  
William J. Andrews ◽  
Swagat Ray ◽  
Tatiana Panova ◽  
Christoph Engel ◽  
Konstantin I. Panov
Keyword(s):  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
3D Structure ◽  
Rrna Synthesis ◽  
Initiation Complex ◽  
Dna Intercalators ◽  
Pol I ◽  
Groove Binders ◽  
In Cells

In eukaryotes, ribosome biogenesis is driven by the synthesis of the ribosomal RNA (rRNA) by RNA polymerase I (Pol-I) and is tightly linked to cell growth and proliferation. The 3D-structure of the rDNA promoter plays an important, yet not fully understood role in regulating rRNA synthesis. We hypothesized that DNA intercalators/groove binders could affect this structure and disrupt rRNA transcription. To test this hypothesis, we investigated the effect of a number of compounds on Pol-I transcription in vitro and in cells. We find that intercalators/groove binders are potent inhibitors of Pol-I specific transcription both in vitro and in cells, regardless of their specificity and the strength of its interaction with DNA. Importantly, the synthetic ability of Pol-I is unaffected, suggesting that these compounds are not targeting post-initiating events. Notably, the tested compounds have limited effect on transcription by Pol-II and III, demonstrating the hypersensitivity of Pol-I transcription. We propose that stability of pre-initiation complex and initiation are affected as result of altered 3D architecture of the rDNA promoter, which is well in line with the recently reported importance of biophysical rDNA promoter properties on initiation complex formation in the yeast system.

scholarly journals Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

2021 ◽  
Author(s):  
Sarah C. Kammerud ◽  
Brandon J. Metge ◽  
Amr R. Elhamamsy ◽  
Shannon E. Weeks ◽  
Heba A. Alsheikh ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Negative Impact ◽  
Rrna Synthesis ◽  
Pol I ◽  
Lung Colonization ◽  
A Cell ◽  
Dietary Flavonoid ◽  
Polymerase I

AbstractThe nucleolus of a cell is a critical cellular compartment that is responsible for ribosome biogenesis and plays a central role in tumor progression. Fisetin, a nutraceutical, is a naturally occurring flavonol from the flavonoid group of polyphenols that has anti-cancer effects. Fisetin negatively impacts several signaling pathways that support tumor progression. However, effect of fisetin on the nucleolus and its functions were unknown. We observed that fisetin is able to physically enter the nucleolus. In the nucleolus, RNA polymerase I (RNA Pol I) mediates the biogenesis of ribosomal RNA. Thus, we investigated the impacts of fisetin on the nucleolus. We observed that breast tumor cells treated with fisetin show a 20–30% decreased nucleolar abundance per cell and a 30–60% downregulation of RNA Pol I transcription activity, as well as a 50–70% reduction in nascent rRNA synthesis, depending on the cell line. Our studies show that fisetin negatively influences MAPK/ERK pathway to impair RNA Pol I activity and rRNA biogenesis. Functionally, we demonstrate that fisetin acts synergistically (CI = 0.4) with RNA Pol I inhibitor, BMH-21 and shows a noteworthy negative impact (60% decrease) on lung colonization of breast cancer cells. Overall, our findings highlight the potential of ribosomal RNA (rRNA) biogenesis as a target for secondary prevention and possible treatment of metastatic disease.

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