Pre-Ribosomal RNA Processing in Human Cells: From Mechanisms to Congenital Diseases

Aubert, Maxime; O’Donohue, Marie-Françoise; Lebaron, Simon; Gleizes, Pierre‐Emmanuel

doi:10.3390/biom8040123

Cited by 85 publications

(104 citation statements)

References 203 publications

(248 reference statements)

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“…In this precursor, the mature rRNAs are flanked by non-coding spacer sequences, which include the 5 and 3 external transcribed spacers (ETS) and internal transcribed spacers (ITS) 1 and 2. These sequences contain several cleavage sites and are gradually eliminated by the sequential action of endo-and exoribonucleases schematically reported in Figure 3C [37]. In the presence of uL3, 48 h of the LQ1 treatment caused an accumulation of about 40% of the 47S pre-rRNA ( Figure 3A).…”

Section: Lq1 Causes Nucleolar Stress and Affects Rrna Processingmentioning

confidence: 95%

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

et al. 2020

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The antiproliferative G-quadruplex aptamers are a promising and challenging subject in the framework of the anticancer therapeutic oligonucleotides research field. Although several antiproliferative G-quadruplex aptamers have been identified and proven to be effective on different cancer cell lines, their mechanism of action is still unexplored. We have recently described the antiproliferative activity of a heterochiral thrombin binding aptamer (TBA) derivative, namely, LQ1. Here, we investigate the molecular mechanisms of LQ1 activity and the structural and antiproliferative properties of two further TBA derivatives, differing from LQ1 only by the small loop base-compositions. We demonstrate that in p53 deleted colon cancer cells, LQ1 causes nucleolar stress, impairs ribosomal RNA processing, leading to the accumulation of pre-ribosomal RNAs, arrests cells in the G2/M phase and induces early apoptosis. Importantly, the depletion of uL3 abrogates all these effects, indicating that uL3 is a crucial player in the mechanism of action of LQ1. Taken together, our findings identify p53-independent and uL3-dependent nucleolar stress as a novel stress response pathway activated by a specific G-quadruplex TBA derivative. To the best of our knowledge, this investigation reveals, for the first time, the involvement of the nucleolar stress pathway in the mechanism of action of antiproliferative G-quadruplex aptamers.

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Section: Lq1 Causes Nucleolar Stress and Affects Rrna Processingmentioning

confidence: 95%

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

et al. 2020

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“…In 47S rRNA precursor, the mature rRNAs are flanked by non-coding spacer sequences, which include the 5 and 3 external transcribed spacers (ETS) and internal transcribed spacers (ITS) 1 and 2. These transcribed spacers contain several cleavage sites and are gradually eliminated by the sequential action of endo-and exo-ribonucleases schematically reported in Figure 1A [23]. Table 1.…”

Section: Alteration Of Ul3 Intracellular Levels Causes Defects In Rrnmentioning

confidence: 99%

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

Pecoraro

Carotenuto

Bazzoli

et al. 2020

IJMS

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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.

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“…Ribosomes are assembled through a hierarchical pathway that comprises a series of folding events, integration of ribosomal proteins and precursor rRNA processing 5 . Assembly begins in the nucleolus where RNA polymerase I transcribes the poly-cistronic pre-rRNA which encodes for the 18S, 5.8S and 28S rRNAs separated by two internal transcribed spacers (ITS1 and ITS2) and flanked by two external transcribed spacers (5¢-ETS and 3¢-ETS) 6 . Efficient and precise removal of these spacers is vital for the functional integrity of the ribosome [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

“…Assembly begins in the nucleolus where RNA polymerase I transcribes the poly-cistronic pre-rRNA which encodes for the 18S, 5.8S and 28S rRNAs separated by two internal transcribed spacers (ITS1 and ITS2) and flanked by two external transcribed spacers (5¢-ETS and 3¢-ETS) 6 . Efficient and precise removal of these spacers is vital for the functional integrity of the ribosome [6][7][8] . Correspondingly, there is a growing list of pre-rRNA processing factors associated with motor neuron diseases 6,[9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

“…Efficient and precise removal of these spacers is vital for the functional integrity of the ribosome [6][7][8] . Correspondingly, there is a growing list of pre-rRNA processing factors associated with motor neuron diseases 6,[9][10][11] . The pre-rRNA processing factor LAS1L is highly expressed in the human cerebellum 12 and mutations are associated with spinal muscle atrophy with respiratory distress (SMARD) and Wilson-Turner X-linked mental retardation syndrome 13,14 .…”

Section: Introductionmentioning

confidence: 99%

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Nol9 is a Spatial Regulator for the Human ITS2 pre-rRNA Processing Complex

Gordon

Pillon

Stanley

2019

Preprint

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The ribosome plays a universal role in translating the cellular proteome. Defects in the ribosome assembly factor Las1L are associated with congenital lethal motor neuron disease and X-linked intellectual disability disorders, yet its role in processing precursor ribosomal RNA (pre-rRNA) is largely unclear. The Las1L endoribonuclease associates with the Nol9 polynucleotide kinase to form the internal transcribed spacer 2 (ITS2) pre-rRNA processing machinery. Together, Las1L-Nol9 catalyzes RNA cleavage and phosphorylation to mark the ITS2 for degradation. While ITS2 processing is critical for the production of functional ribosomes, the regulation of mammalian Las1L-Nol9 remains obscure. Here we characterize the human Las1L-Nol9 complex and identify critical molecular features that regulate its assembly and spatial organization. We establish that Las1L and Nol9 form a higher-order complex and identify the regions responsible for orchestrating this intricate architecture. Structural analysis by highresolution imaging defines the intricate spatial pattern of Las1L-Nol9 within the nucleolar sub-structure linked with late pre-rRNA processing events. Furthermore, we uncover a Nol9 encoded nucleolar localization sequence that is responsible for nucleolar transport of the assembled LasL-Nol9 complex.Together, these data provide a mechanism for the assembly and nucleolar localization of the human ITS2 pre-rRNA processing complex.

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Pre-Ribosomal RNA Processing in Human Cells: From Mechanisms to Congenital Diseases

Cited by 85 publications

References 203 publications

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

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

Nol9 is a Spatial Regulator for the Human ITS2 pre-rRNA Processing Complex

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