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Transcriptome profile of OVCAR3 cells treated with DMSO or THZ531 (200nM) for 6hr

ABSTRACT: Transcription-associated cyclin-dependent kinases (CDKs) regulate the transcription cycle through sequential phosphorylation of the RNA polymerase II (RNAPII). We report that dual inhibition of the highly homologous CDK12 and CDK13 impairs splicing of a subset of promoter-proximal introns characterized by weak 3’ splice sites located at larger distance from the branchpoint. Nascent transcript analysis indicated that these introns are selectively retained upon pharmacologic inhibition of CDK12/13 with respect to downstream introns of the same pre-mRNAs. Retention of these introns was also triggered by Pladienolide B (PdB), an inhibitor of the U2 snRNP factor SF3B1 that recognizes the branchpoint. CDK12/13 activity promotes the interaction of SF3B1 with the RNAPII phosphorylated on serine 2 and disruption of this interaction by treatment with the CDK12/13 inhibitor THZ531 impairs the association of SF3B1 with the chromatin and its recruitment to the 3’ splice site of these introns. Furthermore, by using suboptimal doses of THZ531 and PdB, we describe a synergic effect of these inhibitors on intron retention, cell cycle progression and cancer cell survival. These findings uncover a mechanism by which CDK12/13 couple RNA transcription and processing and suggest that combined inhibition of these kinases and the spliceosome represents an exploitable anticancer approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222493 | GEO | 2023/03/29

REPOSITORIES: GEO

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