Cdk18-KO Mouse

Cdk18, also known as PCTK3, is a cyclin-dependent kinase. It belongs to the PCTAIRE subfamily of CDKs, characterized by a serine-to-cysteine mutation in the consensus PSTAIRE motif. After activation by cyclin A2 or phosphorylation at Ser12 by PKA, it can modulate cargo transport in membrane traffic, regulate p53-responsive genes, and maintain genome integrity [1]. It is involved in pathways related to cell cycle checkpoints and DNA repair mechanisms to ensure genome stability [2].

Depletion of Cdk18 in cells causes an increase in endogenous DNA damage and chromosomal abnormalities. Cdk18-depleted cells accumulate in early S-phase, with retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress [2]. In breast cancer, high Cdk18 protein expression is associated with a triple-negative and basal-like phenotype, as well as improved patient survival, especially in ER-negative breast cancers and those treated with chemotherapy. Also, cells with high levels of endogenous Cdk18 are more sensitive to replication-stress-inducing chemotherapeutic agents [4]. In glioblastoma, MYC-mediated transcriptional repression of Cdk18 generates sensitivity to PARP inhibitors. Cdk18 facilitates ATR activation and homologous recombination, conferring PARP inhibitor resistance [3].

In conclusion, Cdk18 is crucial for maintaining genome stability, especially in relation to replication stress signaling. Its role in diseases such as breast cancer, glioblastoma, and potentially in early ischaemic stroke in sickle-cell-disease patients, as indicated by genetic association studies [5], highlights its importance. Functional studies, especially those using loss-of-function models, have been key in revealing these aspects of Cdk18's biological functions.