scholarly journals Nucleolar Stress Functions Upstream to Stimulate Expression of Autophagy Regulators

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6220
Author(s):  
David P. Dannheisig ◽  
Anna Schimansky ◽  
Cornelia Donow ◽  
Astrid S. Pfister
Keyword(s):  
Ribosome Biogenesis ◽  
Autophagic Flux ◽  
Cancer Therapies ◽  
Growth And Survival ◽  
Cycle Arrest ◽  
Pol I ◽  
Nucleolar Stress ◽  
Stress Functions ◽  
Underlying Mechanisms ◽  
Polymerase I

Ribosome biogenesis is essential for protein synthesis, cell growth and survival. The process takes places in nucleoli and is orchestrated by various proteins, among them RNA polymerases I–III as well as ribosome biogenesis factors. Perturbation of ribosome biogenesis activates the nucleolar stress response, which classically triggers cell cycle arrest and apoptosis. Nucleolar stress is utilized in modern anti-cancer therapies, however, also contributes to the development of various pathologies, including cancer. Growing evidence suggests that nucleolar stress stimulates compensatory cascades, for instance bulk autophagy. However, underlying mechanisms are poorly understood. Here we demonstrate that induction of nucleolar stress activates expression of key autophagic regulators such as ATG7 and ATG16L1, essential for generation of autophagosomes. We show that knockdown of the ribosomopathy factor SBDS, or of key ribosome biogenesis factors (PPAN, NPM, PES1) is associated with enhanced levels of ATG7 in cancer cells. The same holds true when interfering with RNA polymerase I function by either pharmacological inhibition (CX-5461) or depletion of the transcription factor UBF-1. Moreover, we demonstrate that RNA pol I inhibition by CX-5461 stimulates autophagic flux. Together, our data establish that nucleolar stress affects transcriptional regulation of autophagy. Given the contribution of both axes in propagation or cure of cancer, our data uncover a connection that might be targeted in future.

scholarly journals Loss of Peter Pan (PPAN) Affects Mitochondrial Homeostasis and Autophagic Flux

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 894 ◽  
Author(s):  
David P. Dannheisig ◽  
Eileen Beck ◽  
Enrico Calzia ◽  
Paul Walther ◽  
Christian Behrends ◽  
...  
Keyword(s):  
Cellular Response ◽  
Ribosome Biogenesis ◽  
Autophagic Flux ◽  
Inner Mitochondrial Membrane ◽  
Peter Pan ◽  
Atp Production ◽  
Mitochondrial Homeostasis ◽  
Cycle Arrest ◽  
Nucleolar Stress ◽  
Tight Connection

Nucleolar stress is a cellular response to inhibition of ribosome biogenesis or nucleolar disruption leading to cell cycle arrest and/or apoptosis. Emerging evidence points to a tight connection between nucleolar stress and autophagy as a mechanism underlying various diseases such as neurodegeneration and treatment of cancer. Peter Pan (PPAN) functions as a key regulator of ribosome biogenesis. We previously showed that human PPAN localizes to nucleoli and mitochondria and that PPAN knockdown triggers a p53-independent nucleolar stress response culminating in mitochondrial apoptosis. Here, we demonstrate a novel role of PPAN in the regulation of mitochondrial homeostasis and autophagy. Our present study characterizes PPAN as a factor required for maintaining mitochondrial integrity and respiration-coupled ATP production. PPAN interacts with cardiolipin, a lipid of the inner mitochondrial membrane. Down-regulation of PPAN enhances autophagic flux in cancer cells. PPAN knockdown promotes recruitment of the E3-ubiquitin ligase Parkin to damaged mitochondria. Moreover, we provide evidence that PPAN knockdown decreases mitochondrial mass in Parkin-expressing cells. In summary, our study uncovers that PPAN knockdown is linked to mitochondrial damage and stimulates autophagy.

scholarly journals p53 induces a survival transcriptional response after nucleolar stress.

2021 ◽  
pp. mbc.E21-05-0251
Author(s):  
Han Liao ◽  
Anushri Gaur ◽  
Claire Mauvais ◽  
Catherine Denicourt
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Ribosome Biogenesis ◽  
Rrna Synthesis ◽  
Transcriptional Program ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest ◽  
Pol I ◽  
Nucleolar Stress ◽  
Metabolic Remodeling

Accumulating evidence indicate that increased ribosome biogenesis is a hallmark of cancer. It is well established that inhibition of any steps of ribosome biogenesis induces a nucleolar stress characterized by p53 activation and subsequent cell cycle arrest and/or cell death. However, cells derived from solid tumors have demonstrated different degree of sensitivity to ribosome biogenesis inhibition, where cytostatic effects rather than apoptosis are observed. The reason for this is not clear and the p53-specific transcriptional program induced after nucleolar stress has not been previously investigated. Here we demonstrate that blocking rRNA synthesis by depletion of essential rRNA processing factors such as LAS1L, PELP1, and NOP2 or by inhibition of RNA Pol I with the specific small molecule inhibitor CX-5461, mainly induce cell cycle arrest accompanied with autophagy in solid tumor-derived cell lines. Using gene expression analysis, we find that p53 orchestrates a transcriptional program involved in promoting metabolic remodeling and autophagy to help cells survive under nucleolar stress. Importantly, our study demonstrates that blocking autophagy significantly sensitizes cancer cells to RNA Pol I inhibition by CX-5461, suggesting that interfering with autophagy should be considered a strategy to heighten the responsiveness of ribosome biogenesis-targeted therapies in p53-positive tumors.

scholarly journals Translational control during cellular senescence

2020 ◽  
Author(s):  
Matthew J. Payea ◽  
Carlos Anerillas ◽  
Ravi Tharakan ◽  
Myriam Gorospe
Keyword(s):  
Translational Control ◽  
Ribosome Biogenesis ◽  
Rrna Processing ◽  
Proliferating Cells ◽  
Cycle Arrest ◽  
Nucleolar Stress ◽  
Specific Proteins ◽  
Inflammatory Proteins ◽  
Secretory Phenotype

Senescence is a state of long-term cell-cycle arrest that arises in cells that have incurred sub-lethal damage. While senescent cells no longer replicate, they remain metabolically active and further develop unique and stable phenotypes that are not present in proliferating cells. On one hand, senescent cells increase in size, maintain an active mTORC1 complex, and produce and secrete a substantial amount of inflammatory proteins as part of the senescence associated secretory phenotype (SASP). On the other hand, these pro-growth phenotypes contrast with the p53-mediated growth arrest typical of senescent cells that is associated with nucleolar stress and an inhibition of rRNA processing and ribosome biogenesis. In sum, translation in senescent cells paradoxically comprises both a global repression of translation triggered by DNA damage and a select increase in the translation of specific proteins, including SASP factors.

scholarly journals Structure and function of ribosomal RNA gene chromatin

2008 ◽  
Vol 36 (4) ◽  
pp. 619-624 ◽  
Author(s):  
Joanna L. Birch ◽  
Joost C.B.M. Zomerdijk
Keyword(s):  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Pol I ◽  
And Function ◽  
Polymerase I ◽  
Cell Growth And Proliferation ◽  
Cellular Control

Transcription of the major ribosomal RNAs by Pol I (RNA polymerase I) is a key determinant of ribosome biogenesis, driving cell growth and proliferation in eukaryotes. Hundreds of copies of rRNA genes are present in each cell, and there is evidence that the cellular control of Pol I transcription involves adjustments to the number of rRNA genes actively engaged in transcription, as well as to the rate of transcription from each active gene. Chromatin structure is inextricably linked to rRNA gene activity, and the present review highlights recent advances in this area.

scholarly journals The dynamic assembly of distinct RNA polymerase I complexes modulates rDNA transcription

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Eva Torreira ◽  
Jaime Alegrio Louro ◽  
Irene Pazos ◽  
Noelia González-Polo ◽  
David Gil-Carton ◽  
...  
Keyword(s):  
Cell Growth ◽  
Rna Polymerase ◽  
Ribosome Biogenesis ◽  
Mutational Analysis ◽  
Rna Polymerase I ◽  
Initiation Factor ◽  
Rdna Transcription ◽  
Pol I ◽  
Polymerase I

Cell growth requires synthesis of ribosomal RNA by RNA polymerase I (Pol I). Binding of initiation factor Rrn3 activates Pol I, fostering recruitment to ribosomal DNA promoters. This fundamental process must be precisely regulated to satisfy cell needs at any time. We present in vivo evidence that, when growth is arrested by nutrient deprivation, cells induce rapid clearance of Pol I–Rrn3 complexes, followed by the assembly of inactive Pol I homodimers. This dual repressive mechanism reverts upon nutrient addition, thus restoring cell growth. Moreover, Pol I dimers also form after inhibition of either ribosome biogenesis or protein synthesis. Our mutational analysis, based on the electron cryomicroscopy structures of monomeric Pol I alone and in complex with Rrn3, underscores the central role of subunits A43 and A14 in the regulation of differential Pol I complexes assembly and subsequent promoter association.

scholarly journals Ribosomal RNA Transcription Regulation in Breast Cancer

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 502
Author(s):  
Cecelia M. Harold ◽  
Amber F. Buhagiar ◽  
Yan Cheng ◽  
Susan J. Baserga
Keyword(s):  
Breast Cancer ◽  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Rna Polymerase I ◽  
Cancer Therapies ◽  
Rdna Transcription ◽  
Global Protein Synthesis ◽  
Novel Drugs ◽  
Polymerase I

Ribosome biogenesis is a complex process that is responsible for the formation of ribosomes and ultimately global protein synthesis. The first step in this process is the synthesis of the ribosomal RNA in the nucleolus, transcribed by RNA Polymerase I. Historically, abnormal nucleolar structure is indicative of poor cancer prognoses. In recent years, it has been shown that ribosome biogenesis, and rDNA transcription in particular, is dysregulated in cancer cells. Coupled with advancements in screening technology that allowed for the discovery of novel drugs targeting RNA Polymerase I, this transcriptional machinery is an increasingly viable target for cancer therapies. In this review, we discuss ribosome biogenesis in breast cancer and the different cellular pathways involved. Moreover, we discuss current therapeutics that have been found to affect rDNA transcription and more novel drugs that target rDNA transcription machinery as a promising avenue for breast cancer treatment.

scholarly journals Drosophila to Explore Nucleolar Stress

2021 ◽  
Vol 22 (13) ◽  
pp. 6759
Author(s):  
Kathryn R. DeLeo ◽  
Sonu S. Baral ◽  
Alex Houser ◽  
Allison James ◽  
Phelan Sewell ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Treacher Collins Syndrome ◽  
P Bodies ◽  
Disease States ◽  
Cycle Arrest ◽  
Nucleolar Stress ◽  
Marker Proteins ◽  
Drosophila Larvae ◽  
Disc Cells ◽  
Eye Imaginal Disc

Nucleolar stress occurs when ribosome production or function declines. Nucleolar stress in stem cells or progenitor cells often leads to disease states called ribosomopathies. Drosophila offers a robust system to explore how nucleolar stress causes cell cycle arrest, apoptosis, or autophagy depending on the cell type. We provide an overview of nucleolar stress in Drosophila by depleting nucleolar phosphoprotein of 140 kDa (Nopp140), a ribosome biogenesis factor (RBF) in nucleoli and Cajal bodies (CBs). The depletion of Nopp140 in eye imaginal disc cells generates eye deformities reminiscent of craniofacial deformities associated with the Treacher Collins syndrome (TCS), a human ribosomopathy. We show the activation of c-Jun N-terminal Kinase (JNK) in Drosophila larvae homozygous for a Nopp140 gene deletion. JNK is known to induce the expression of the pro-apoptotic Hid protein and autophagy factors Atg1, Atg18.1, and Atg8a; thus, JNK is a central regulator in Drosophila nucleolar stress. Ribosome abundance declines upon Nopp140 loss, but unusual cytoplasmic granules accumulate that resemble Processing (P) bodies based on marker proteins, Decapping Protein 1 (DCP1) and Maternal expression at 31B (Me31B). Wild type brain neuroblasts (NBs) express copious amounts of endogenous coilin, but coilin levels decline upon nucleolar stress in most NB types relative to the Mushroom body (MB) NBs. MB NBs exhibit resilience against nucleolar stress as they maintain normal coilin, Deadpan, and EdU labeling levels.

scholarly journals Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

2019 ◽  
Author(s):  
E. P. Kusnadi ◽  
A. S. Trigos ◽  
C. Cullinane ◽  
D. L. Goode ◽  
O. Larsson ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Single Agent ◽  
Acquired Resistance ◽  
Cellular Metabolism ◽  
Mrna Translation ◽  
Pol I ◽  
Polymerase I

AbstractElevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA Polymerase I (Pol I) transcription, revealed single agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here we show that this improved efficacy is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this co-treatment is driven by translational re-wiring that results in dysregulated cellular metabolism and induction of a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies identify the molecular mechanisms underpinning the response of blood cancers to selective ribosome biogenesis inhibitors and identify metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.

scholarly journals Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells

2020 ◽  
Vol 21 (6) ◽  
pp. 2143 ◽  
Author(s):  
Annalisa Pecoraro ◽  
Pietro Carotenuto ◽  
Brunella Franco ◽  
Rossella De Cegli ◽  
Giulia Russo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Ribosome Biogenesis ◽  
Chemotherapeutic Agents ◽  
Rrna Synthesis ◽  
Autophagic Flux ◽  
Colon Cancer Cells ◽  
Nucleolar Stress ◽  
Autophagic Process

The nucleolus is the site of ribosome biogenesis and has been recently described as important sensor for a variety of cellular stressors. In the last two decades, it has been largely demonstrated that many chemotherapeutics act by inhibiting early or late rRNA processing steps with consequent alteration of ribosome biogenesis and activation of nucleolar stress response. The overall result is cell cycle arrest and/or apoptotic cell death of cancer cells. Our previously data demonstrated that ribosomal protein uL3 is a key sensor of nucleolar stress activated by common chemotherapeutic agents in cancer cells lacking p53. We have also demonstrated that uL3 status is associated to chemoresistance; down-regulation of uL3 makes some chemotherapeutic drugs ineffective. Here, we demonstrate that in colon cancer cells, the uL3 status affects rRNA synthesis and processing with consequent activation of uL3-mediated nucleolar stress pathway. Transcriptome analysis of HCT 116p53−/− cells expressing uL3 and of a cell sub line stably depleted of uL3 treated with Actinomycin D suggests a new extra-ribosomal role of uL3 in the regulation of autophagic process. By using confocal microscopy and Western blotting experiments, we demonstrated that uL3 acts as inhibitory factor of autophagic process; the absence of uL3 is associated to increase of autophagic flux and to chemoresistance. Furthermore, experiments conducted in presence of chloroquine, a known inhibitor of autophagy, indicate a role of uL3 in chloroquine-mediated inhibition of autophagy. On the basis of these results and our previous findings, we hypothesize that the absence of uL3 in cancer cells might inhibit cancer cell response to drug treatment through the activation of cytoprotective autophagy. The restoration of uL3 could enhance the activity of many drugs thanks to its pro-apoptotic and anti-autophagic activity.

Regulation of RNA Polymerase I Transcription in Development, Disease, and Aging

2018 ◽  
Vol 87 (1) ◽  
pp. 51-73 ◽  
Author(s):  
Samim Sharifi ◽  
Holger Bierhoff
Keyword(s):  
Ribosome Biogenesis ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Environmental Signals ◽  
Pol I ◽  
Nuclear Rna ◽  
Multicopy Genes ◽  
Polymerase I ◽  
Precursor Transcript

Ribosome biogenesis is a complex and highly energy-demanding process that requires the concerted action of all three nuclear RNA polymerases (Pol I–III) in eukaryotes. The three largest ribosomal RNAs (rRNAs) originate from a precursor transcript (pre-rRNA) that is encoded by multicopy genes located in the nucleolus. Transcription of these rRNA genes (rDNA) by Pol I is the key regulation step in ribosome production and is tightly controlled by an intricate network of signaling pathways and epigenetic mechanisms. In this article, we give an overview of the composition of the basal Pol I machinery and rDNA chromatin. We discuss rRNA gene regulation in response to environmental signals and developmental cues and focus on perturbations occurring in diseases linked to either excessive or limited rRNA levels. Finally, we discuss the emerging view that rDNA integrity and activity may be involved in the aging process.

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