The AAA+ ATPAse RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA481496 | ENA |
REPOSITORIES: ENA
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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
Project description: Not available
| S-EPMC6887538 | biostudies-literature
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
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: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
Project description:A functional cooperation between an AAA type ATPase domain and a bromodomain has been evidenced. These two domains were identified and their activity tested in a yet uncharacterized factor, named Atad2, whose two-domain configuration remained highly conserved during evolution. In human and mouse, Atad2 is most abundantly expressed in testis and in the mouse. It has also been detected in post-meiotic stages and in mature spermatozoa. The AAA-ATPase domain was found necessary for protein multimerization and high affinity binding to acetylated nucleosomes by its bromodomain. The binding was found specific to acetylated histone H4 tail with a critical role for the acetylated K5 position. In vivo studies show that Atad2 behaves as a general repressor of transcription and possesses a chromatin “freezing” activity. Finally, we demonstrate that the induction of apoptosis leads to an early degradation of Atad2, which probably facilitates the action of apoptotic factors by increasing chromatin dynamics.
2009-10-01 | GSE12279 | GEO
Project description:RUVBL2 is most important AAA+ ATPase for RNA polymerase II assembly and transcription regulation, through DNA remodeling or by directly interaction with PIC，this study will comprehensively to study the promiscuous functions of this proteins through the ChIP-MS, ChIP-seq, RNA-seq and nascent RNA seq and biochemistry analysis. Our study would provide more systematic and novel responsibility of this molecule, especially for the development and carcinomas.
2022-09-29 | PXD036528 | Pride
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 | GSE160738 | 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 | GSE160698 | 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