Cdk18-flox Mouse

Cdk18, also known as PCTK3, is a member of the cyclin-dependent kinase (CDK) family. Its catalytic activity requires a cyclin regulatory subunit. Cdk18 is involved in several important biological functions such as modulating cargo transport in membrane traffic, being a p53-responsive gene, and regulating genome integrity. It is also associated with pathways like the regulation of replication stress signaling and the FAK/Rho signaling pathway [1,2,4].

Depletion of Cdk18 in cells causes an increase in endogenous DNA damage, chromosomal abnormalities, and cells accumulate in early S-phase with retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress. Mechanistically, it interacts with RAD9, RAD17 and TOPBP1, and its deficiency leads to a decrease in RAD17 and RAD9 chromatin retention during 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, and cells with high endogenous Cdk18 expression show increased sensitivity to replication-stress-inducing chemotherapeutic agents [5]. In glioblastoma, MYC-mediated transcriptional repression of Cdk18 generates sensitivity to PARP inhibitors, and Cdk18 promotes ATR activation and homologous recombination to mediate PARP inhibitor resistance [3].

In conclusion, Cdk18 plays a crucial role in maintaining genome stability, especially in regulating replication stress signaling. Its dysregulation is related to various diseases such as cancer, cerebral ischemia, and metabolic diseases. Studies using cell-based loss-of-function experiments and analysis of its expression in human cancer tissues have provided insights into its functions in disease conditions, highlighting its potential as a target for drug design.