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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)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141372 | GEO | 2020/04/29

REPOSITORIES: GEO

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

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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.

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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.

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

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Quant-seq analysis of differential polyadenylation site usages in caused by different Pol II mutants with slow elongation rates in Flp-In-293 cells and dual inhibition of CDK12 and CDK13 by THZ531 HEK293T cells

Project description:We used 3' RNA-Seq to determine the effects of slow elongating Pol II on polyadenatltion site usages, also the effects of CDK12 and CDK13 inhibition caused by THZ531 on alternative polyadenylation

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Project description:CDK12 and CDK13

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DRB-PRO-Seq for measuring Pol II transcriptional elongation rate alterations upon inhibition of analog sensitive CDK12 and/or CDK13

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2020-04-29 | GSE141373 | GEO

Transcriptome map of nascent RNA production alterations upon CDK9 and analog senstiveCDK12 and/or CDK13 inhibition (TT-Seq)

Project description:We performed TT-Seq on MV4;11 WT, CDK12AS/NULL, CDK13AS/AS, #1CDK12AS/NULL;CDK13AS/NULL and #2CDK12AS/NULL;CDK13AS/AS MV4;11 clones treated with 1-NM-PP1 or vehicle for 25 mintues to identify the effect of CDK12 and/or CDK13 on nasenct RNA production.

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