CDK12

CDK12 is a human serine/threonine protein kinase in the cyclin-dependent kinase family. It forms an active complex with Cyclin K (CCNK) to regulate transcription and genome stability. The kinase phosphorylates serine 2 residues on the C-terminal domain (CTD) of RNA polymerase II, promoting transcription elongation and co-transcriptional RNA processing. CDK12 activity is associated with regulation of long, gene-rich transcripts and with control of alternative polyadenylation and mRNA maturation.

Beyond transcription, CDK12 plays a prominent role in the cellular DNA damage response. By sustaining expression of a set of DNA damage response genes—such as BRCA1, BRCA2, RAD51, and others—the CDK12–Cyclin K complex supports homologous recombination and genome integrity. Loss or reduction of CDK12 function can compromise DDR gene expression and contribute to genomic instability, with potential sensitivities to DNA damaging agents.

Clinical significance: Somatic alterations of CDK12 have been identified in various cancers, most notably ovarian and prostate cancers. These alterations can be associated with a distinctive pattern of genomic changes, including focal tandem duplications, and may influence response to PARP inhibitors or other DNA-damaging therapies.

Therapeutic research: CDK12 and CDK13 inhibitors are being explored in preclinical and early clinical studies as cancer therapeutics. Selective inhibition aims to disrupt DDR gene expression and exploit synthetic lethality in CDK12-mutant tumors.