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RBM7 activates P-TEFb for a pro-survival transcriptional response to DNA damage

ABSTRACT: RBM7 activates P-TEFb for a pro-survival transcriptional response to DNA damage

PROVIDER: PRJEB24882 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR2286892.fastq.gz	Fastqsanger.gz
	ERR2286893.fastq.gz	Fastqsanger.gz
	ERR2286894.fastq.gz	Fastqsanger.gz
	ERR2286895.fastq.gz	Fastqsanger.gz
	ERR2286896.fastq.gz	Fastqsanger.gz

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RBM7 activates P-TEFb for a pro-survival transcriptional response to DNA damage

Project description:DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain obscure. Here we show that following DNA damage, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) elongation and increases cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by DNA damage-enhanced binding of RBM7 to 7SK, the scaffold of the 7SK small nuclear ribonucleoprotein (snRNP) that inhibits P-TEFb. As a result, P-TEFb relocates from 7SK snRNP to chromatin to activate transcription of key DDR genes and multiple classes of non-coding RNAs. By alleviating the inhibition of P-TEFb, RBM7 thus promotes Pol II elongation to activate a transcriptional response that is crucial for cell fate upon genotoxic insult. Our work highlights a novel paradigm in stress-dependent control of Pol II pause release, and offers the promise of combating cancer by RBM7 and P-TEFb antagonists in combination with established DNA damage-inducing chemotherapeutics.

2018-06-01 | E-MTAB-6475 | biostudies-arrayexpress

Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis

Project description:Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis

| PRJNA716616 | ENA

Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis

Project description:Tumor metastasis remains one of the major causes of cancer-related deaths in patients with solid tumors. Mechanisms by which metabolic alterations regarding pro-survival lipid signaling activation in inducing cancer cell migration and metastasis are largely unknown. Here, we demonstrate that S1P metabolism activates endogenous complement signaling for inducing tumor metastasis via inducing inflammasome-mediated pro-inflammation. Our studies using molecular, pharmacologic and genetic tools showed that activation of sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P/S1PR1) induces tumor metastasis via enhanced intracellular complement signaling by the regulation of the C3-PPIL1 complex and subsequent inflammasome activation in cancer cells and in vivo xenograft-derived tumors.

2022-03-23 | GSE169443 | GEO

P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

Project description:P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

| PRJNA894501 | ENA

Inhibition of CDK12 induces cancer cell dependence on activated P-TEFb via the ATM-stimulated p53 and NF-kB transcriptional programs

Project description:P-TEFb and CDK12 facilitate transcription elongation by RNA polymerase II and play prominent roles in cancer. Understanding their functional interplay could inform novel anti-cancer strategies. While inhibition of CDK12 downregulates unique sets of genes, eliciting genomic instability that is being exploited for novel therapies, little is known about the significance of transcriptional induction in CDK12-targeted cells. We show that inhibition of CDK12 in colon cancer-derived cells activates P-TEFb and induces genes of key cancer signaling pathways, including p53 and NF-kB. Mechanistically, cancer cells become exquisitely dependent on P-TEFb through activation of p53-dependent apoptosis and attenuation of NF-kB-dependent proliferation. Furthermore, we show that the DNA damage-responsive ATM kinase mediates these effects. While ATM is required for the synthetic lethality of CDK12 and P-TEFb co-targeting in p53-proficient cells, co-inhibition of ATM and CDK12 synergizes in decreasing viability of p53-deficient cells. Finally, pairwise targeting of CDK12, P-TEFb and transcription initiation kinase CDK7 stimulates p53-dependent apoptosis of cancer cell spheroids. We propose that the stimulation of Pol II pause release by P-TEFb at the signal-responsive genes underlies the dependence of CDK12-targeted cancer cells on P-TEFb. Together, our work provides a rationale for combinatorial targeting of CDK12 and P-TEFb or the induced oncogenic pathways in cancer.

2023-09-17 | GSE236803 | GEO

T-bet recruits P-TEFb to super-enhancers to regulate T helper cell differentiation (Agilent 2)

Project description:The transcription factor T-bet induces differentiation of CD4+ T cells into the Th1 lineage and also allows for a degree of functional plasticity. Here, we show that T-bet acts through super-enhancers to recruit the elongation factor P-TEFb. Th1-specific genes are poised for activation in Th2 cells and P-TEFb recruitment activates transcriptional elongation. T-bet also induces extensive P-TEFb binding at super-enhancers, where it acts to stimulate enhancer RNA transcription. P-TEFb inhibition selectively blocks activation of lineage-specific genes and reverses Th1-associated retinitis pathology. T-bet-mediated recruitment of P-TEFb to super-enhancers at otherwise poised genes provides a model for how lineage-specifying factors promote differentiation towards specific cell fates whilst maintaining a degree of functional plasticity. Transcriptional profiling of mouse Th1 and Th2 cells treated with JQ1, which inhibits P-TEFb recruitment, or the P-TEFb inhibitor Flavopiridol vs DMSO conrol treated cells. Goal was to identify genes which are sensitive to P-TEFb inhibition.

2016-06-08 | GSE62485 | GEO

The 7SK/P-TEFb snRNP controls ultraviolet radiation-induced transcriptional reprogramming

Project description:Releasing promoter-proximally-paused RNA polymerase II (RNAPII) by the positive transcription elongation factor b (P-TEFb) is a central regulatory step of eukaryotic mRNA synthesis. The nuclear activity of P-TEFb is controlled mainly by the 7SK small nuclear RNP (snRNP) which sequesters active P-TEFb into inactive 7SK/P-TEFb snRNP. Here we demonstrate that under normal culture conditions, the lack of 7SK snRNP has only a minor impact on global RNAPII transcription and promoter-proximal pausing without detectable consequences on cell growth and proliferation. However, upon ultraviolet (UV) light-induced DNA damage, cells lacking 7SK have a defective transcriptional response and highly reduced viability. Both UV-induced release of ‘lesion-scanning’ polymerases and activation of key early responsive genes are compromised in the absence of 7SK. We show that proper induction of 7SK-dependent UV-responsive genes, namely efficient release of paused RNAPII and recruitment of key elongation factors, requires P-TEFb activity directly mobilized from the nucleoplasmic 7SK/P-TEFb snRNP.

2021-03-30 | GSE147055 | GEO

T-bet recruits P-TEFb to super-enhancers to regulate T helper cell differentiation (RNA-Seq)

2016-06-08 | GSE62483 | GEO

P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

Project description:We used RNA sequencing to deciphere a molecular basis for the synthethic lethality of non-genotoxic p53 activation and P-TEFb inhibition.

2022-12-30 | GSE216610 | GEO

Monoamine oxidase-dependent pro-survival signaling in diabetic hearts

Project description:Monoamine oxidase-dependent pro-survival signaling in diabetic hearts

| PRJNA866484 | ENA