Cyclin K (CCNK) (CCNK)

Cyclin K (CCNK) is a regulatory cyclin that predominantly exists as the 65-kDa isoform (cyclin K1) across human tissues, encoded by alternative splicing of the CCNK gene. It forms distinct complexes with cyclin-dependent kinase 12 (CDK12) or CDK13, stabilizing these kinases and enabling their phosphorylation of serine 2 in the C-terminal domain (CTD) of RNA polymerase II. This activity drives transcriptional elongation and expression of DNA damage response genes (e.g., BRCA1, ATR), maintaining genomic stability. CDK12/Cyclin K has a unique structure with a C-terminal kinase extension in CDK12 that enhances ATP binding and substrate specificity, particularly for Ser7-prephosphorylated CTD. Depletion of Cyclin K mimics CDK12 loss, causing overlapping phenotypes like genomic instability and reduced Ser2 phosphorylation. Recent molecular glues exploit the CDK12/Cyclin K interface to recruit DDB1-CUL4 E3 ligase for Cyclin K ubiquitination and degradation, offering potential cancer therapeutic strategies despite on-target risks like DNA repair defects

Other names

Cyclin K1 (predominant 65-kDa isoform)CycKcyclin K1

Forms heterodimeric complex with CDK12 (or CDK13) to activate kinase activity for CTD Ser2 phosphorylation of RNA polymerase II; promotes transcriptional elongation of specific genes; targeted degradation via molecular glues that bridge CDK12 to DDB1-CUL4 E3 ligase complex, leading to ubiquitination and proteasomal degradation of cyclin K