Analysis of gene expression change in cancer cells induced by nucleolar stress
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE174729 | GEO | 2021/05/20
REPOSITORIES: GEO
Similar Datasets
Project description:FuHsi Maintains Nucleolar Structure and Initiates Nucleolar Biogenesis.
| PRJNA1068033 | ENA
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 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:We identify a previously uncharacterized human nucleoli-enriched protein FuHsi. FuHsi is an essential nucleolar molecule that regulates nucleolar biogenesis and mouse development.
2024-08-02 | GSE253977 | GEO
Project description:Ribosome biogenesis is a complex and energy demanding process requiring tight coordination with cell growth and proliferation. Impairment of ribosome biogenesis activates a well-defined cell-cycle checkpoint that primarily relies on the activation of p53 signaling. However, there is mounting evidence that p53-independent signaling networks connect impaired ribosome biogenesis to cell cycle-checkpoints. So far, however, these pathways have remained largely enigmatic. By characterizing the nucleolar SUMO isopeptidase SENP3 and SENP5 we found that both isopeptidases control the SUMOylation state of specific ribosome biogenesis factors and regulate the 60S and 40S ribosome maturation pathways. Accordingly, inactivation of SENP3 and SENP5 induces a canonical p53-mediated G1/S arrest. Intriguingly, however, we discovered that inactivation of SENP3 or SENP5 drastically and specifically downregulates the expression of the key-cell cycle regulator CDK6 in a p53-independent process. Accordingly, depletion of SENP3 or SENP5 impairs G1/S transition and cell proliferation in both p53-proficient and p53-deficient cells. Strikingly, we further revealed that impaired ribosome maturation induced by depletion of a panel of ribosome biogenesis factors or by chemical inhibition of RNA polymerase I, generally triggers loss of CDK6 independent of the cellular p53 status. Altogether our data unveil a long-sought p53-independent checkpoint of impaired ribosome biogenesis. Since CDK6 represents a dependency in a subset of cancer entities, such as AML and lymphoma, we propose that this checkpoint can serve as an actionable drug target in tumor therapy.
2023-10-28 | PXD037796 | Pride
Project description:Ribosome biogenesis is a complex and energy demanding process requiring tight coordination with cell growth and proliferation. Impairment of ribosome biogenesis activates a well-defined cell-cycle checkpoint that primarily relies on the activation of p53 signaling. However, there is mounting evidence that p53-independent signaling networks connect impaired ribosome biogenesis to cell cycle-checkpoints. So far, however, these pathways have remained largely enigmatic. By characterizing the nucleolar SUMO isopeptidase SENP3 and SENP5 we found that both isopeptidases control the SUMOylation state of specific ribosome biogenesis factors and regulate the 60S and 40S ribosome maturation pathways. Accordingly, inactivation of SENP3 and SENP5 induces a canonical p53-mediated G1/S arrest. Intriguingly, however, we discovered that inactivation of SENP3 or SENP5 drastically and specifically downregulates the expression of the key-cell cycle regulator CDK6 in a p53-independent process. Accordingly, depletion of SENP3 or SENP5 impairs G1/S transition and cell proliferation in both p53-proficient and p53-deficient cells. Strikingly, we further revealed that impaired ribosome maturation induced by depletion of a panel of ribosome biogenesis factors or by chemical inhibition of RNA polymerase I, generally triggers loss of CDK6 independent of the cellular p53 status. Altogether our data unveil a long-sought p53-independent checkpoint of impaired ribosome biogenesis. Since CDK6 represents a dependency in a subset of cancer entities, such as AML and lymphoma, we propose that this checkpoint can serve as an actionable drug target in tumor therapy.
2023-10-28 | PXD037793 | Pride
Project description:Ribosome biogenesis is a complex and energy demanding process requiring tight coordination with cell growth and proliferation. Impairment of ribosome biogenesis activates a well-defined cell-cycle checkpoint that primarily relies on the activation of p53 signaling. However, there is mounting evidence that p53-independent signaling networks connect impaired ribosome biogenesis to cell cycle-checkpoints. So far, however, these pathways have remained largely enigmatic. By characterizing the nucleolar SUMO isopeptidase SENP3 and SENP5 we found that both isopeptidases control the SUMOylation state of specific ribosome biogenesis factors and regulate the 60S and 40S ribosome maturation pathways. Accordingly, inactivation of SENP3 and SENP5 induces a canonical p53-mediated G1/S arrest. Intriguingly, however, we discovered that inactivation of SENP3 or SENP5 drastically and specifically downregulates the expression of the key-cell cycle regulator CDK6 in a p53-independent process. Accordingly, depletion of SENP3 or SENP5 impairs G1/S transition and cell proliferation in both p53-proficient and p53-deficient cells. Strikingly, we further revealed that impaired ribosome maturation induced by depletion of a panel of ribosome biogenesis factors or by chemical inhibition of RNA polymerase I, generally triggers loss of CDK6 independent of the cellular p53 status. Altogether our data unveil a long-sought p53-independent checkpoint of impaired ribosome biogenesis. Since CDK6 represents a dependency in a subset of cancer entities, such as AML and lymphoma, we propose that this checkpoint can serve as an actionable drug target in tumor therapy.
2023-10-28 | PXD037800 | Pride
Project description:Ribosome biogenesis is a complex and energy demanding process requiring tight coordination with cell growth and proliferation. Impairment of ribosome biogenesis activates a well-defined cell-cycle checkpoint that primarily relies on the activation of p53 signaling. However, there is mounting evidence that p53-independent signaling networks connect impaired ribosome biogenesis to cell cycle-checkpoints. So far, however, these pathways have remained largely enigmatic. By characterizing the nucleolar SUMO isopeptidase SENP3 and SENP5 we found that both isopeptidases control the SUMOylation state of specific ribosome biogenesis factors and regulate the 60S and 40S ribosome maturation pathways. Accordingly, inactivation of SENP3 and SENP5 induces a canonical p53-mediated G1/S arrest. Intriguingly, however, we discovered that inactivation of SENP3 or SENP5 drastically and specifically downregulates the expression of the key-cell cycle regulator CDK6 in a p53-independent process. Accordingly, depletion of SENP3 or SENP5 impairs G1/S transition and cell proliferation in both p53-proficient and p53-deficient cells. Strikingly, we further revealed that impaired ribosome maturation induced by depletion of a panel of ribosome biogenesis factors or by chemical inhibition of RNA polymerase I, generally triggers loss of CDK6 independent of the cellular p53 status. Altogether our data unveil a long-sought p53-independent checkpoint of impaired ribosome biogenesis. Since CDK6 represents a dependency in a subset of cancer entities, such as AML and lymphoma, we propose that this checkpoint can serve as an actionable drug target in tumor therapy.
2023-10-28 | PXD043556 | Pride
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
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 | GSE232857 | GEO