As the new millennium began, CDK12 and CDK13 were discovered as nucleotide sequences that encode protein kinases related to cell cycle CDKs. By the end of the first decade both proteins had been qualified as CTD kinases, and it was emerging that both are heterodimers containing a Cyclin K subunit. Since then, many studies on CDK12 have shown that, through phosphorylating the CTD of transcribing RNAPII, it plays critical roles in several stages of gene expression, notably RNA processing; it is also crucial for maintaining genome stability. Fewer studies on CKD13 have clearly shown that it is functionally distinct from CDK12. CDK13 is important for proper expression of a number of genes, but it also probably plays yet-to-be-discovered roles in other processes. This review summarizes much of the work on CDK12 and CDK13 and attempts to evaluate the results and place them in context. Our understanding of these two enzymes has begun to mature, but we still have much to learn about both. An indicator of one major area of medically-relevant future research comes from the discovery that CDK12 is a tumor suppressor, notably for certain ovarian and prostate cancers. A challenge for the future is to understand CDK12 and CDK13 well enough to explain how their loss promotes cancer development and how we can intercede to prevent or treat those cancers. Abbreviations: CDK: cyclin-dependent kinase; CTD: C-terminal repeat domain of POLR2A; CTDK-I: CTD kinase I (yeast); Ctk1: catalytic subunit of CTDK-I; Ctk2: cyclin-like subunit of CTDK-I; PCAP: phosphoCTD-associating protein; POLR2A: largest subunit of RNAPII; SRI domain: Set2-RNAPII Interacting domain.
Keywords: C-terminal repeat domain; CTD; CTD phosphorylation; RNA polymerase II; co-transcriptional processes.