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A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence (CRISPRi screen)

ABSTRACT: Oncogene-induced senescence is an important tumor suppressor mechanism that limits proliferation of cells harboring oncogenic mutations. Through a genome-wide screen, we discovered a conserved snoRNA, SNORA13, that is required for this pathway. Although SNORA13 guides the pseudouridylation of a highly conserved nucleotide in the ribosomal decoding center, loss of this snoRNA minimally impacts translation. Instead, we found that SNORA13 negatively regulates ribosome biogenesis. Oncogenic stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. We showed that SNORA13 interacts directly with RPL23, decreasing its incorporation into maturing 60S subunits and, consequently, increasing the pool of free RPs, thereby promoting the p53-mediated senescence program. Thus, SNORA13 regulates ribosome biogenesis and the p53 pathway through a non-canonical mechanism distinct from its role in guiding RNA modification. These findings expand our understanding of snoRNA functions and the roles of these abundant noncoding RNAs in cellular signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232856 | GEO | 2024/07/01

REPOSITORIES: GEO

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A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence (Ribosome profiling)

Project description:Oncogene-induced senescence is an important tumor suppressor mechanism that limits proliferation of cells harboring oncogenic mutations. Through a genome-wide screen, we discovered a conserved snoRNA, SNORA13, that is required for this pathway. Although SNORA13 guides the pseudouridylation of a highly conserved nucleotide in the ribosomal decoding center, loss of this snoRNA minimally impacts translation. Instead, we found that SNORA13 negatively regulates ribosome biogenesis. Oncogenic stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. We showed that SNORA13 interacts directly with RPL23, decreasing its incorporation into maturing 60S subunits and, consequently, increasing the pool of free RPs, thereby promoting the p53-mediated senescence program. Thus, SNORA13 regulates ribosome biogenesis and the p53 pathway through a non-canonical mechanism distinct from its role in guiding RNA modification. These findings expand our understanding of snoRNA functions and the roles of these abundant noncoding RNAs in cellular signaling.

2024-07-01 | GSE232858 | GEO

A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence (RNA-sequencing)

2024-07-01 | GSE232857 | GEO

A ribosome assembly stress response regulates transcription to maintain proteome homeostasis

Project description:Ribosome biogenesis is a complex and energy-demanding process requiring tight coordination of ribosomal RNA (rRNA) and ribosomal protein (RP) production. Alteration of any step in this process may impact growth by leading to proteotoxic stress. Although the transcription factor Hsf1 has emerged as a central regulator of proteostasis, how its activity is coordinated with ribosome biogenesis is unknown. Here we show that arrest of ribosome biogenesis in the budding yeast S. cerevisiae triggers rapid activation of a highly specific stress pathway that coordinately up-regulates Hsf1 target genes and down-regulates RP genes. Activation of Hsf1 target genes requires neo-synthesis of RPs, which accumulate in an insoluble fraction, leading to sequestration of the RP transcriptional activator Ifh1. Our data suggest that levels of newly-synthetized RPs, imported into the nucleus but not yet assembled into ribosomes, work to continuously balance Hsf1 and Ifh1 activity, thus guarding against proteotoxic stress during ribosome assembly.

2019-06-24 | GSE125226 | GEO

The 40S-LARP1 complex reprograms the cellular translatome upon mTOR inhibition to preserve the protein synthetic capacity

Project description:Ribosomes execute the transcriptional program in every cell. Critical to sustain nearly all cellular activities, ribosome biogenesis requires the translation of ~200 factors of which 80 are ribosomal proteins (RPs). As ribosome synthesis depends on RP mRNAs translation, a priority within the translatome architecture should exist to ensure the preservation of ribosome biogenesis capacity, particularly under adverse growth conditions. Here we show that under critical metabolic constraints characterized by mTOR inhibition, LARP1 complexed with the 40S subunit protects from ribophagy the mRNAs regulon for ribosome biogenesis and protein synthesis, acutely preparing the translatome to promptly resume ribosomes production after growth conditions return permissive. Characterizing the LARP1-protected translatome revealed a set of 5’TOP transcript isoforms other than RPs involved in energy production and in mitochondrial function, among other processes, indicating that the mTOR-LARP1-5’TOP axis acts at the translational level as a primary guardian of the cellular anabolic capacity

2021-10-30 | GSE186779 | GEO

p53 activation during ribosome biogenesis regulates normal erythroid differentiation. [expression]

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

p53 activation during ribosome biogenesis regulates normal erythroid differentiation. [ChIP-Seq]

2020-09-14 | GSE157208 | GEO

Ribosome biogenesis controls suture mesenchymal stem cell fate via selective regulation ofcomplement pathway in to prevent craniosynostosis [Ribo-seq]

Project description:Suture mesenchymal stem cell (MSC) drives calvarial suture development, homeostasis, and regeneration. Its loss leads to craniosynostosis, a prevailing craniofacial disorder characterized by premature suture closure. Ribosome biogenesis, historically thought to be a static house-keeping process, is now known to have tissue-specific roles. However, the functional specificity of ribosome biogenesis in suture MSCs remains largely unexplored, hampering development of therapeutic strategies for craniofacial tissue regeneration. We genetically perturb ribosome biogenesis using Snord118, a small nucleolar RNA (snoRNA) required for ribosomal RNA (rRNA) maturation. MSC specific conditional knockout (cKO) of Snord118 in mice leads to p53 activation, cell death, mesenchymal and MSC loss, impaired osteogenic and osteoclastic activity, resulting in suture growth and craniosynostosis defects. Using our newly established human induced pluripotent stem cell (iPSC)-derived MSCs combined with ribosome profiling, we found that SNORD118deficiency in MSCs causes global translation dysregulations and downregulation of complement pathway, a part of innate immune system with selective but poorly characterized physiological functions in craniofacial tissue homeostasis. Overall, ribosome biogenesis controls suture MSC fate via selective regulation of complement pathway.

2023-12-20 | GSE223615 | GEO

Ribosome biogenesis controls suture mesenchymal stem cell fate via selective regulation of complement pathway in to prevent craniosynostosis [RNA-seq]

2023-12-20 | GSE223614 | GEO

A translation control module coordinates germline stem cell differentiation with ribosome biogenesis during Drosophila oogenesis [rRNA_RIP-seq]

Project description:Ribosomal defects perturb stem cell differentiation, causing diseases called ribosomopathies. How ribosome levels control stem cell differentiation is not fully known. Here, we discovered three RNA helicases are required for ribosome biogenesis and for Drosophila oogenesis. Loss of these helicases, which we named Aramis, Athos and Porthos, lead to aberrant stabilization of p53, cell cycle arrest and stalled GSC differentiation. Unexpectedly, Aramis is required for efficient translation of a cohort of mRNAs containing a 5’-Terminal-Oligo-Pyrimidine (TOP)-motif, including mRNAs that encode ribosomal proteins and a conserved p53 inhibitor, Novel Nucleolar protein 1 (Non1). The TOP-motif co-regulates the translation of growth-related mRNAs in mammals. As in mammals, the La-related protein co-regulates the translation of TOP-motif containing RNAs during Drosophila oogenesis. Thus, a previously unappreciated TOP-motif in Drosophila responds to reduced ribosome biogenesis to co-regulate the translation of ribosomal proteins and a p53 repressor, thus coupling ribosome biogenesis to GSC differentiation.

2022-03-24 | GSE171347 | GEO

A translation control module coordinates germline stem cell differentiation with ribosome biogenesis during Drosophila oogenesis [Polysome-seq]

2022-03-24 | GSE171349 | GEO

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