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

Abstract

Cancer: Phosphorylating enzyme may provide therapeutic target Better understanding of the roles played by a protein kinase, an enzyme that adds phosphate groups to other molecules, in healthy and diseased states may help scientists identify novel cancer treatments. Cyclin-dependent kinases (CDKs) are a family of protein kinases crucial to cell cycling and gene expression. CDK12 can activate and modulate cancer-related gene expression, but, according to a review by Seung Hyuk Choi and colleagues at the Salk Institute for Biological Studies in La Jolla, USA, further investigations into its exact functioning and control mechanisms are required. CDK12 mutations are frequently found in aggressive breast and ovarian cancers, while loss of CDK12 function results in abnormal expression of DNA damage response genes and genome instability. CDK12 may also regulate drug resistance in cancer cells. The team suggests that therapies targeting CDK12 are worth exploring. 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.