RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer
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ABSTRACT:
PROVIDER: PRJNA420950 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10734268_1.fastq.gz | Fastqsanger.gz | |||
| SRR10734268_2.fastq.gz | Fastqsanger.gz | |||
| SRR10734269_1.fastq.gz | Fastqsanger.gz | |||
| SRR10734269_2.fastq.gz | Fastqsanger.gz | |||
| SRR10734270_1.fastq.gz | Fastqsanger.gz |
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Project description:RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression prognostic of poor survival. Utilizing a highly specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of their ATPase activity impedes RPA loading at replication forks, decreases fork stability, and ultimately results in replication catastrophe and cancer cell death. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development.
2019-12-18 | GSE107637 | GEO
Project description:RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression associated with poor survival. Utilizing a specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation or dissociation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of its ATPase activity can cause S-phase arrest, which culminates in cancer cell death via replication catastrophe. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development.
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Project description:To understand its role RUVBL1/2 in neuroblastoma, we inhibited RUVBL1/2 ATPase activity two independent cell lines, SK-N-AS and CBL-BA, with 250 nM CB-6644 at 0, 24, 48, and 72 hrs and performed RNA sequencing.
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Project description:Transcription regulators and apparatuses compartmentalize into transcriptional condensates in part through molecular interactions among intrinsically disordered regions. To better understand how these fundamental condensates are regulated, we performed time-series analyses of transcriptome, genome and imaging to show that the previously characterized molecular chaperone RUVBL2 assembles Pol II condensates by its ATPase activity and prevalently interacting with diverse oncogenic transcription factors at promoters, thereby maintaining active transcription in mammalian cells. Besides, RUVBL2 is overexpressed in various cancers, has higher expression levels and preferential chromatin binding compared with RUVBL1. Remarkably, acute protein degradation and chemical perturbations of RUVBL2 with the nucleoside compound cordycepin result in the repression of oncogenes in embryonic stem cells and breast cancer cells, respectively. Our results suggest that molecular chaperone RUVBL2 safeguards the hemostasis of transcriptional condensates at promoters. Thus, pharmacological perturbations of RUVBL2 is a promising strategy to restore these condensates in breast cancers.
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Project description:Transcription regulators and apparatuses compartmentalize into transcriptional condensates in part through molecular interactions among intrinsically disordered regions. To better understand how these fundamental condensates are regulated, we performed time-series analyses of transcriptome, genome and imaging to show that the previously characterized molecular chaperone RUVBL2 assembles Pol II condensates by its ATPase activity and prevalently interacting with diverse oncogenic transcription factors at promoters, thereby maintaining active transcription in mammalian cells. Besides, RUVBL2 is overexpressed in various cancers, has higher expression levels and preferential chromatin binding compared with RUVBL1. Remarkably, acute protein degradation and chemical perturbations of RUVBL2 with the nucleoside compound cordycepin result in the repression of oncogenes in embryonic stem cells and breast cancer cells, respectively. Our results suggest that molecular chaperone RUVBL2 safeguards the hemostasis of transcriptional condensates at promoters. Thus, pharmacological perturbations of RUVBL2 is a promising strategy to restore these condensates in breast cancers.
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Project description:Transcription regulators and apparatuses compartmentalize into transcriptional condensates in part through molecular interactions among intrinsically disordered regions. To better understand how these fundamental condensates are regulated, we performed time-series analyses of transcriptome, genome and imaging to show that the previously characterized molecular chaperone RUVBL2 assembles Pol II condensates by its ATPase activity and prevalently interacting with diverse oncogenic transcription factors at promoters, thereby maintaining active transcription in mammalian cells. Besides, RUVBL2 is overexpressed in various cancers, has higher expression levels and preferential chromatin binding compared with RUVBL1. Remarkably, acute protein degradation and chemical perturbations of RUVBL2 with the nucleoside compound cordycepin result in the repression of oncogenes in embryonic stem cells and breast cancer cells, respectively. Our results suggest that molecular chaperone RUVBL2 safeguards the hemostasis of transcriptional condensates at promoters. Thus, pharmacological perturbations of RUVBL2 is a promising strategy to restore these condensates in breast cancers.
2022-08-30 | GSE160696 | GEO
Project description:Transcription regulators and apparatuses compartmentalize into transcriptional condensates in part through molecular interactions among intrinsically disordered regions. To better understand how these fundamental condensates are regulated, we performed time-series analyses of transcriptome, genome and imaging to show that the previously characterized molecular chaperone RUVBL2 assembles Pol II condensates by its ATPase activity and prevalently interacting with diverse oncogenic transcription factors at promoters, thereby maintaining active transcription in mammalian cells. Besides, RUVBL2 is overexpressed in various cancers, has higher expression levels and preferential chromatin binding compared with RUVBL1. Remarkably, acute protein degradation and chemical perturbations of RUVBL2 with the nucleoside compound cordycepin result in the repression of oncogenes in embryonic stem cells and breast cancer cells, respectively. Our results suggest that molecular chaperone RUVBL2 safeguards the hemostasis of transcriptional condensates at promoters. Thus, pharmacological perturbations of RUVBL2 is a promising strategy to restore these condensates in breast cancers.
2022-08-30 | GSE185347 | GEO
Project description:Objective: The hallmark oncogene MYC drives the progression of most tumorstumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). Design: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumorstumours in mice.Results:Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumorstumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumortumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immuno-evasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. Conclusion: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.
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Project description:Objective: The hallmark oncogene MYC drives the progression of most tumorstumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). Design: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumorstumours in mice.Results:Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumorstumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumortumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immuno-evasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. Conclusion: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.
2024-06-01 | GSE216091 | GEO
Project description:Objective: The hallmark oncogene MYC drives the progression of most tumorstumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). Design: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumorstumours in mice.Results:Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumorstumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumortumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immuno-evasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. Conclusion: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.
2024-06-01 | GSE264280 | GEO