CDK12/13 promote splicing of proximal introns by enhancing the interaction between RNA polymerase II and the splicing factor SF3B1

Transcription-associated cyclin-dependent kinases (CDKs) regulate the transcription cycle through sequential phosphorylation of RNA polymerase II (RNAPII). Herein, 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 pharmacological 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 small nucelar ribonucleoprotein (snRNP) factor SF3B1 that recognizes the branchpoint. CDK12/13 activity promotes the interaction of SF3B1 with RNAPII phosphorylated on Ser2, and disruption of this interaction by treatment with the CDK12/13 inhibitor THZ531 impairs the association of SF3B1 with 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.

 

Comments：

The article reports that two closely related cyclin-dependent kinases (CDKs), CDK12 and CDK13, are involved in regulating the splicing of a subset of introns located near the promoter region of genes. These introns have weak 3' splice sites and are located further away from the branchpoint, making them more difficult to splice. Pharmacological inhibition of CDK12/13 or treatment with pladienolide B, an inhibitor of the spliceosome factor SF3B1, leads to the selective retention of these introns in nascent transcripts.

CDK12/13 activity promotes the interaction of SF3B1 with RNA polymerase II phosphorylated on Ser2, and disruption of this interaction by treatment with the CDK12/13 inhibitor THZ531 impairs the association of SF3B1 with chromatin and its recruitment to the 3' splice site of these introns. The study also shows that combining suboptimal doses of THZ531 and PdB has a synergic effect on intron retention, cell cycle progression, and cancer cell survival.

Overall, the study uncovers a mechanism by which CDK12/13 couple RNA transcription and processing and suggests that targeting both CDK12/13 and the spliceosome could be an effective approach for anticancer therapy.

Related Products

Cat.No.	Product Name	Information
S6595	THZ531	THZ531 is a selective covalent inhibitor of CDK12 and CDK13 with IC50 values of 158 and 69 nM, respectively.

Related Targets

CDK