CDK12

CDK12 is a transcription-associated cyclin-dependent kinase that forms a complex with cyclin K and phosphorylates the C-terminal domain of RNA polymerase II to support transcription elongation and RNA processing^[1][1]. CDK12 preferentially maintains the expression of long genes enriched in the DNA damage response (DDR), including BRCA1, ATR, FANCI, and FANCD2, thereby preserving genomic stability under replication and genotoxic stress^[1][2][3]. Mechanistically, CDK12 regulates transcription elongation, co-transcriptional splicing, transcription termination, and RNA turnover, and its inhibition induces premature cleavage and polyadenylation of DDR transcripts, leading to selective suppression of DNA repair pathways^[2][4][5]. In cancer models, CDK12 deficiency or inhibition impairs homologous recombination-associated repair programs, increases DNA damage signaling, and enhances sensitivity to DNA-damaging agents and PARP inhibitors^[2][5][6]. Compared with the closely related kinase CDK13, which shares cyclin K as a regulatory partner and participates broadly in transcriptional regulation, CDK12 shows a more prominent role in sustaining DDR gene expression and genome maintenance^[1][1]. For experimental applications, dual CDK12/CDK13 inhibitors such as THZ531 and SR-4835 have been widely used to investigate transcriptional dependencies, DDR regulation, and therapeutic vulnerabilities in cancer cells^[1][7].