Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107637 | GEO | 2019/12/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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

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

| PRJNA420950 | ENA

Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [Mnase-seq]

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

Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [ChIP-Seq]

2022-08-30 | GSE160738 | GEO

Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [RNA-Seq]

2022-08-30 | GSE160698 | GEO

Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [PRO-Seq]

2022-08-30 | GSE160696 | GEO

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

Project description: Not available

| S-EPMC8048778 | biostudies-literature

Expression analysis of THP1 cells following shRNA knock-down of RUVBL2

Project description:We used an inducible shRNA system and RNA-Seq to examine gene expression changes in acute myeloid leukemia THP1 cells following silencing of RUVBL2. RUVBL2 is a AAA+ ATPase that functions in a number of cellular processes, including chromatin remodeling and trnascriptional control, and is critical for survival of acute myeloid leukemia cells and in vivo disease progression.

2018-10-31 | GSE105253 | GEO

Gene expression changes in THP1 cells at day 2 and 4 following shRNA knock-down of RUVBL2

Project description:We used an inducible shRNA system and RNA-Seq to examine gene expression changes in acute myeloid leukemia THP1 cells following silencing of RUVBL2. RUVBL2 is a AAA+ ATPase that functions in a number of cellular processes, including chromatin remodeling and transcriptional control, and is critical for survival of acute myeloid leukemia cells and in vivo disease progression.

2019-01-01 | GSE117106 | GEO

The AAA+ ATPAse RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia

Project description:Subtype-specific leukemia oncogenes drive aberrant gene expression profiles that converge on common essential mediators to ensure leukemia self-renewal and inhibition of differentiation. The transcription factor c-MYB functions as one such mediator in a diverse range of leukemias. Here we show that transcriptional repression of myeloid differentiation associated c-MYB target genes in AML is enforced by the AAA+ ATPAse RUVBL2. Silencing RUVBL2 expression resulted in increased binding of c-MYB to these loci and their transcriptional derepression. RUVBL2 inhibition induced AML cell apoptosis and severely impaired disease progression of established AML in engrafted mice. In contrast, such inhibition had little impact on normal hematopoietic progenitor differentiation. These data reveal a central mechanism governing inhibition of myeloid differentiation by c-MYB in AML. They also indicate that targeting the control of c-MYB function by RUVBL2 is likely to be a promising approach to developing future anti-AML therapies.

2020-04-14 | GSE117224 | GEO

NOPCHAP1 is a PAQosome cofactor that helps loading NOP58 on RUVBL1/2 during box C/D snoRNP biogenesis

Project description:The PAQosome is a large complex composed of the HSP90/R2TP chaperone and a prefoldin-like module. It promotes the biogenesis of cellular machineries but it is unclear how it discriminates closely related client proteins. Among the main PAQosome clients are C/D snoRNPs and in particular their core protein NOP58. Using NOP58 mutants and proteomic experiments, we identify different assembly intermediates and show that C12ORF45, which we rename NOPCHAP1, acts as a bridge between NOP58 and PAQosome. NOPCHAP1 makes direct physical interactions with the CC-NOP domain of NOP58 and domain II of RUVBL1/RUVBL2 AAA+ ATPases. Interestingly, NOPCHAP1 interaction with RuvBL1/2 is disrupted upon ATP binding. Moreover, while it robustly binds both yeast and human NOP58, it makes little interactions with NOP56 and PRPF31, two other closely related CC-NOP proteins. Expression of NOP58, but not NOP56 or PRPF31, is decreased in NOPCHAP1 KO cells. We propose that NOPCHAP1 is a client-loading PAQosome cofactor that selects NOP58 to promote box C/D snoRNP assembly.

2020-12-11 | GSE161155 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data