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RUVBL1 and RUVBL2 as novel druggable DNA Damage Response regulators in the MYCN regulatory network in neuroblastoma

ABSTRACT: RUVBL1 and RUVBL2 as novel druggable DNA Damage Response regulators in the MYCN regulatory network in neuroblastoma

PROVIDER: PRJEB63991 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR11639900_1.fastq.gz	Fastqsanger.gz
	ERR11639900_2.fastq.gz	Fastqsanger.gz
	ERR11639901_1.fastq.gz	Fastqsanger.gz
	ERR11639901_2.fastq.gz	Fastqsanger.gz
	ERR11639902_1.fastq.gz	Fastqsanger.gz

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RUVBL1 and RUVBL2 are druggable MYCN regulators in neuroblastoma

Project description:RUVBL1 and RUVBL2 are druggable MYCN regulators in neuroblastoma

| PRJNA1375842 | ENA

RUVBL1 and RUVBL2 are druggable MYCN regulators in neuroblastoma

Project description:High-risk neuroblastoma (NB), accounting for approximately 50% of all cases, exhibits high relapse rates and life-threatening toxicities despite intensive therapies, highlighting the need for safer and more effective treatments. Analysis of publicly available NB transcriptomic datasets identified RUVBL2 as a key node in the MYC(N) regulatory network. High MYC signature scores were observed in high-risk NB cohorts, and multivariate Cox regression analysis showed that RUVBL1/2 expression is an independent predictor of both overall and event-free survival. Experimental validation through cell culture, western blotting, qPCR, and RNA-seq demonstrated that knockdown or pharmacological inhibition of RUVBL1/2 using CB-6644 induced replication stress, leading to cell cycle arrest, DNA damage, and apoptosis. Mechanistically, RUVBL1/2 regulated ATR and ATM protein stability and transcriptionally controlled MYC(N) expression. These findings indicate that RUVBL1 and RUVBL2 are novel regulators of the DNA damage response with both therapeutic and prognostic potential in high-risk NB.

2025-12-22 | GSE312769 | GEO

RUVBL1 and RUVBL2 as novel druggable DNA Damage Response regulators in the MYCN regulatory network in neuroblastoma

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.

2024-08-31 | E-MTAB-13137 | biostudies-arrayexpress

RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer

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

siRNA-mediated knockdown of RUVBL1 and RUVBL2 in CLB-BAR neuroblastoma cells

Project description:siRNA-mediated knockdown of RUVBL1 and RUVBL2 in CLB-BAR neuroblastoma cells

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KLF5 interacts with RUVBL1/2 to activate classical and basal lineage identities in PDAC [CRISPR]

Project description:We identify KLF5 as a lineage master regulator and a dependency in classical and basal subtypes of human PDAC. We integrate proteomic and genetic screens to reveal RUVBL1 and RUVBL2 as transcriptional coactivators of KLF5 in PDAC. We use biochemical and epigenomic methods to validate that KLF5-RUVBL1/2 complexes directly activate lineage identity genes in PDAC.

2025-10-08 | GSE295348 | GEO

KLF5 interacts with RUVBL1/2 to activate classical and basal lineage identities in PDAC [ChIP-seq]

2025-10-08 | GSE295354 | GEO

KLF5 interacts with RUVBL1/2 to activate classical and basal lineage identities in PDAC [RNA-seq]

2025-10-08 | GSE295349 | GEO

KLF5 interacts with RUVBL1/2 to activate classical and basal lineage identities in PDAC [SLAM-seq]

2025-10-08 | GSE295347 | GEO

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2

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 | GSE216095 | GEO

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