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Characterization of human CDK12 and CDK13 in the regulation of RNA processing

ABSTRACT: We report the total RNA-seq results after CDK9, CDK12 and CDK13 depletion in human HCT116 cells for three days. RNA-seq was performed in cells using two non-targeting replicates and two different shRNAs for each CDK knockdown. For each CDK knockdown, most of the differentially expressed genes were down-regulated with a very small subset of genes upregulated. Different CDK proteins control distinct subsets of genes in vivo, with CDK12 and CDK13 sharing more overlap in function compared to CDK9. Besides, CDK12 and CDK13 loss preferentially affects DNA damage response and snRNA gene expression, respectively.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58107 | GEO | 2014/12/01

SECONDARY ACCESSION(S): PRJNA248918

REPOSITORIES: GEO

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CDK12 and CDK13

Project description:CDK12 and CDK13

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CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

Project description:The RNA polymerase II (POLII) driven transcription cycle is tightly regulated at distinct checkpoints through cyclin dependent kinases (CDKs) and their cognate Cyclins. The molecular events underpinning transcriptional elongation and processivity and CDK-Cyclins involved remain poorly understood. Using CRISPR-CAS9 homology-directed-repair we generated analog-sensitive-kinase variants of CDK12 and CDK13 to probe their individual and shared biological and molecular roles. Single inhibition of CDK12 or CDK13 induced transcriptional responses associated with DNA-damage and cellular growth signaling pathways respectively, with minimal effects on cell viability. In contrast, dual-kinase inhibition potently induced cell death, which was associated with extensive genome-wide transcriptional changes including wide-spread use of alternative 3’ polyadenylation sites. At the molecular level dual-kinase inhibition resulted in the loss of POLII CTD phosphorylation and greatly reduced POLII elongation rates and processivity. These data define significant redundancy between CDK12 and CDK13, and identify both as fundamental regulators of global POLII processivity and transcription elongation.

2020-04-30 | PXD015453 | Pride

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors [Affymetrix]

Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

2016-08-29 | GSE72022 | GEO

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors [ChIP-Seq]

2016-05-19 | GSE72023 | GEO

Transcriptome wide analysis of differential gene expression and polyadenylation site usages caused by inhibition of CDK12 and/or CDK13 in MV4;11 cells (3’ Quant-seq)

Project description:We used 3' RNA-Seq to determine the effects of analog senstive CDK12, CDK13 and dual inhibition on gene expression and polyadenatltion site usages, and to test the redundancy between CDK12 and CDK13 in maintaining global transcrition on the tramcrotpomte level.

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PolyA-sequencing in IMR-32 neuroblastoma cells with shRNA mediated depletion of CDK12, CDK13 or GFP.

Project description:We performed RNA-seq analysis of polA transcripts in IMR-32 cells with shRNA-mediated depletion of CDK12 and CDK13 and GFP as a control

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Quant-seq analysis to determine the effects of CDK12 and CDK13 inhibition by THZ531 in alternative polyadenylation

Project description:We performed 3' Quant-seq on MV4;11 cells after 6 hours treatment of THZ531 to determine whether CDK12 and CDK13 inhibtion cause alternative polyadenlation

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Transcriptome wide alternative splicing analysis to determine the effect of CDK12 and CDK13 inhibition by THZ531 in alternative splicing (Total RNA-Seq)

Project description:We performed Total RNA-seq on MV4;11 cells after 6 hours treatment of THZ531 to determine whether CDK12 and CDK13 inhibtion to cause splicing defects.

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Quant-seq analysis of differential gene expression and polyadenylation site usages in caused by inhibition of CDK12 and CDK13 using THZ531 in THP-1 cells (3’ Quant-seq)

Project description:We used 3' RNA-Seq to determine effect of dual inhibition of CDK12 and CDK13 on gene expression and polyadenatltion site usages in THP-1 cells

2020-04-29 | GSE141376 | GEO

DRB-PRO-Seq for measuring Pol II transcriptional elongation rate alteration up on CDK12 and CDK13 inhibition by THZ531

Project description:We performed PRO-Seq to measure the Pol II elongation rate by measruing the distance of Pol II travels at viarous time points after relased from DRB induced pausing. We compared DMSO/DRB or THZ531/DRB co-treated sample to assess the effect of CDK12 and CDK13 inhibtion by THZ531 on transcriptional elongation rate.

2020-04-29 | GSE141370 | GEO

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