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
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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.
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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.
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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.
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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.
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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.
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Project description:Nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. Its role in regulating stem cell fate is unclear. Here, we present multiple lines of evidence that nucleolar stress induced by interfering rRNA biogenesis can drive two-cell stage embryo-like (2C-like) transcriptional program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, the liquid-liquid phase separation (LLPS) mediated by rRNA and nucleolar proteins maintains the formation of peri-nucleolar heterochromatin (PNH). When mES cells undergo rRNA biogenesis defect, the normal LLPS of nucleolus is disrupted, causing deconjugation of NCL/TRIM28 complex on PNH and changes of epigenetic state and 3D structure of PNH, which leads to Dux, a conserved multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals, to be released from the PNH region, activation of 2C-like program and transition of mES cells to 2C-like cells. Embryos with rRNA biogenesis defect are incompatible to develop from 2-cell (2C) to blastocyte (BC) and appear to skew from the blastocyst to earlier cleavage embryo signatures. Our results highlight that nucleolar LLPS-mediated 3D chromatin structure reshaping of PNH compartment regulates the fate transition of mES cells to 2C-like cells. Our findings for the first time elucidate the novel roles of rRNA biogenesis in regulating the 2C-like and ES state homeostasis in cultured cells and suggest that rRNA biogenesis is a new molecular switch from nucleolus-unmatured 2C stage to nucleolus-matured BC stage during murine pre-implantation embryo development.
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Project description:Nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. Its role in regulating stem cell fate is unclear. Here, we present multiple lines of evidence that nucleolar stress induced by interfering rRNA biogenesis can drive two-cell stage embryo-like (2C-like) transcriptional program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, the liquid-liquid phase separation (LLPS) mediated by rRNA and nucleolar proteins maintains the formation of peri-nucleolar heterochromatin (PNH). When mES cells undergo rRNA biogenesis defect, the normal LLPS of nucleolus is disrupted, causing deconjugation of NCL/TRIM28 complex on PNH and changes of epigenetic state and 3D structure of PNH, which leads to Dux, a conserved multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals, to be released from the PNH region, activation of 2C-like program and transition of mES cells to 2C-like cells. Embryos with rRNA biogenesis defect are incompatible to develop from 2-cell (2C) to blastocyte (BC) and appear to skew from the blastocyst to earlier cleavage embryo signatures. Our results highlight that nucleolar LLPS-mediated 3D chromatin structure reshaping of PNH compartment regulates the fate transition of mES cells to 2C-like cells. Our findings for the first time elucidate the novel roles of rRNA biogenesis in regulating the 2C-like and ES state homeostasis in cultured cells and suggest that rRNA biogenesis is a new molecular switch from nucleolus-unmatured 2C stage to nucleolus-matured BC stage during murine pre-implantation embryo development.
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