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

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.