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A PP2A-Integrator complex regulates transcriptional pause-release by functionally opposing CDK9

ABSTRACT: A PP2A-Integrator complex regulates transcriptional pause-release by functionally opposing CDK9

PROVIDER: PRJNA607046 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13577528_1.fastq.gz	Fastqsanger.gz
	SRR13577528_2.fastq.gz	Fastqsanger.gz
	SRR13577529_1.fastq.gz	Fastqsanger.gz
	SRR13577529_2.fastq.gz	Fastqsanger.gz
	SRR13577530_1.fastq.gz	Fastqsanger.gz

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

Project description:Gene expression by RNA Polymerase II (RNAPII) is tightly controlled by Cyclindependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The RNAPII pausing checkpoint, engaged after transcription initiation, is controlled by CDK9 to regulate transcription in metazoans. We discovered that CDK9-mediated RNAPII pause-release is functionally opposed by a protein phosphatase 2A (PP2A) complex. PP2A dynamically competes for key CDK9 substrates, DSIF and RNAPIICTD, and is recruited to transcription pausing sites by the Integrator complex subunit INTS6. INTS6 depletion confers resistance to CDK9 inhibition in a variety of normal and tumor cell lines. Loss of INTS6 abolishes the Integrator-PP2A association leading to unrestrained CDK9 activity, which amplifies transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill MLLrearranged leukemias and solid tumors and provide therapeutic benefit in vivo. These data demonstrate that finely-tuned gene expression relies on the balance of kinase and phosphatase activity at the pausing checkpoint.

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [ChIP-seq]

Project description:Gene expression by RNA Polymerase II (RNAPII) is tightly controlled by Cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The RNAPII pausing checkpoint, engaged after transcription initiation, is controlled by CDK9 to regulate transcription in metazoans. We discovered that CDK9-mediated RNAPII pause-release is functionally opposed by a protein phosphatase 2A (PP2A) complex. PP2A dynamically competes for key CDK9 substrates, DSIF and RNAPII-CTD, and is recruited to transcription pausing sites by the Integrator complex subunit INTS6. INTS6 depletion confers resistance to CDK9 inhibition in a variety of normal and tumor cell lines. Loss of INTS6 abolishes the Integrator-PP2A association leading to unrestrained CDK9 activity, which amplifies transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill MLL-rearranged leukemias and solid tumors and provide therapeutic benefit in vivo. These data demonstrate that f inely-tuned gene expression relies on the balance of kinase and phosphatase activity at the pausing checkpoint.

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [3UTR-seq]

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [4sU-seq]

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

Project description:A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

Project description:In this study, we discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonises phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates and amplification of acute cell growth and pro-inflammatory transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that finely-tuned gene expression relies on the balance of kinase and phosphatase activity throughout the transcription cycle.

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A PP2A-Integrator complex regulates transcriptional pause-release by functionally opposing CDK9

Project description:We investigated the function of the Integrator Complex and PP2A during transcription.

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [ChIP-seq]

Project description:A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [ChIP-seq]

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [4sU-seq]

Project description:A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [4sU-seq]

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A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [3UTR-seq]

Project description:A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [3UTR-seq]