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Genome-wide changes in RNAPII occupancy, RNAPII phosphorylation, and transcription in response to CDK12/13 inhibition in gliomas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186311 | GEO | 2026/01/29

REPOSITORIES: GEO

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Genome-wide changes in RNAPII occupancy and phosphorylation in response to CDK12/13 inhibition in gliomas

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Genome-wide changes in RNAPII occupancy, RNAPII phosphorylation, and transcription in response to CDK12/13 inhibition in gliomas

Project description:Genome-wide changes in RNAPII occupancy, RNAPII phosphorylation, and transcription in response to CDK12/13 inhibition in gliomas

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Genome-wide changes in RNAPII occupancy and phosphorylation in response to CDK12/13 inhibition in gliomas

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Nascent transcriptome changes in response to CDK12/13 inhibition in gliomas

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Nascent transcriptome changes in response to CDK12/13 inhibition in gliomas

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Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13.

Project description:High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 - a chemical inhibiting CDK7, CDK12, and CDK13 - markedly downregulates MYC. Notably, abolishing MYC expression cannot be achieved by targeting CDK7 alone, but requires the combined inhibition of CDK7, CDK12, and CDK13. In 11 patient-derived xenografts models derived from heavily pre-treated ovarian cancer patients, administration of THZ1 induces significant tumor growth inhibition with concurrent abrogation of MYC expression. Our study indicates that targeting these transcriptional CDKs with agents such as THZ1 may be an effective approach for MYC-dependent ovarian malignancies.

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Project description:Cyclin-dependent kinase 12 (CDK12) interacts with cyclin K to form a functional nuclear kinase that promotes processive transcription elongation through phosphorylation of the C-terminal domain of RNA polymerase II (Pol II). To gain a comprehensive understanding of CDK12's cellular function, we used chemical genetic and phosphoproteomic screening to identify a landscape of nuclear human CDK12 substrates, including regulators of transcription, chromatin organization, and RNA splicing. We further validated LEO1, a subunit of the polymerase-associated factor 1 complex (PAF1C), as a bona fide cellular substrate of CDK12. Acute depletion of LEO1, or substituting LEO1 phosphorylation sites with alanine, attenuated PAF1C association with elongating Pol II and impaired processive transcription elongation. Moreover, we discovered that LEO1 interacts with and is dephosphorylated by the Integrator-PP2A complex (INTAC) and that INTAC depletion promotes the association of PAF1C with Pol II. Together, this study reveals an uncharacterized role for CDK12 and INTAC in regulating LEO1 phosphorylation, providing important insights into gene transcription and its regulation.

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