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Gene expression regulation by CDK12: a versatile kinase in cancer with functions beyond CTD phosphorylation.

ABSTRACT: Cyclin-dependent kinases (CDKs) play critical roles in cell cycle progression and gene expression regulation. In human cancer, transcription-associated CDKs can activate oncogenic gene expression programs, whereas cell cycle-regulatory CDKs mainly induce uncontrolled proliferation. Cyclin-dependent kinase 12 (CDK12) belongs to the CDK family of serine/threonine kinases and has been recently found to have multiple roles in gene expression regulation and tumorigenesis. Originally, CDK12 was thought to be one of the transcription-associated CDKs, acting with its cyclin partner Cyclin K to promote the phosphorylation of the C-terminal domain (CTD) of RNA polymerase II and induce transcription elongation. However, recent studies have demonstrated that CDK12 also controls multiple gene expression processes, including transcription termination, mRNA splicing, and translation. Most importantly, CDK12 mutations are frequently found in human tumors. Loss of CDK12 function causes defective expression of DNA damage response (DDR) genes, which eventually results in genome instability, a hallmark of human cancer. Here, we discuss the diverse roles of CDK12 in gene expression regulation and human cancer, focusing on newly identified CDK12 kinase functions in cellular processes and highlighting CDK12 as a promising therapeutic target for human cancer treatment.

SUBMITTER: Choi SH

PROVIDER: S-EPMC7272620 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Gene expression regulation by CDK12: a versatile kinase in cancer with functions beyond CTD phosphorylation.

Choi Seung Hyuk SH Kim Seongjae S Jones Katherine A KA

Experimental & molecular medicine 20200525 5

Cyclin-dependent kinases (CDKs) play critical roles in cell cycle progression and gene expression regulation. In human cancer, transcription-associated CDKs can activate oncogenic gene expression programs, whereas cell cycle-regulatory CDKs mainly induce uncontrolled proliferation. Cyclin-dependent kinase 12 (CDK12) belongs to the CDK family of serine/threonine kinases and has been recently found to have multiple roles in gene expression regulation and tumorigenesis. Originally, CDK12 was though ...[more]

PMID: 32451425

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Project description:Drosophila contains one (dCDK12) and humans contain two (hCDK12 and hCDK13) proteins that are the closest evolutionary relatives of yeast Ctk1, the catalytic subunit of the major elongation-phase C-terminal repeat domain (CTD) kinase in Saccharomyces cerevisiae, CTDK-I. However, until now, neither CDK12 nor CDK13 has been demonstrated to be a bona fide CTD kinase. Using Drosophila, we demonstrate that dCDK12 (CG7597) is a transcription-associated CTD kinase, the ortholog of yCtk1. Fluorescence microscopy reveals that the distribution of dCDK12 on formaldehyde-fixed polytene chromosomes is virtually identical to that of hyperphosphorylated RNA polymerase II (RNAPII), but is distinct from that of P-TEFb (dCDK9 + dCyclin T). Chromatin immunoprecipitation (ChIP) experiments confirm that dCDK12 is present on the transcribed regions of active Drosophila genes. Compared with P-TEFb, dCDK12 amounts are lower at the 5' end and higher in the middle and at the 3' end of genes (both normalized to RNAPII). Appropriately, Drosophila dCDK12 purified from nuclear extracts manifests CTD kinase activity in vitro. Intriguingly, we find that cyclin K is associated with purified dCDK12, implicating it as the cyclin subunit of this CTD kinase. Most importantly, we demonstrate that RNAi knockdown of dCDK12 in S2 cells alters the phosphorylation state of the CTD, reducing its Ser2 phosphorylation levels. Similarly, in human HeLa cells, we show that hCDK13 purified from nuclear extracts displays CTD kinase activity in vitro, as anticipated. Also, we find that chimeric (yeast/human) versions of Ctk1 containing the kinase homology domains of hCDK12/13 (or hCDK9) are functional in yeast cells (and also in vitro); using this system, we show that a bur1(ts) mutant is rescued more efficiently by a hCDK9 chimera than by a hCDK13 chimera, suggesting the following orthology relationships: Bur1 ? CDK9 and Ctk1 ? CDK12/13. Finally, we show that siRNA knockdown of hCDK12 in HeLa cells results in alterations in the CTD phosphorylation state. Our findings demonstrate that metazoan CDK12 and CDK13 are CTD kinases, and that CDK12 is orthologous to yeast Ctk1.

Dataset Information

Gene expression regulation by CDK12: a versatile kinase in cancer with functions beyond CTD phosphorylation.

Publications

Gene expression regulation by CDK12: a versatile kinase in cancer with functions beyond CTD phosphorylation.

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