CDK18-dependent phosphoregulation and the DNA damage response

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Organisms have evolved phosphorylation mechanisms to sense and repair damaged DNA to support healthy ageing across the lifecourse. Nevertheless, cell cycle and ageing are strongly associated with accumulated breaks and mutations. The DNA damage response (DDR) detects and responds to such lesions. We recently identified a novel human cyclin-dependent kinase (CDK18) as a DDR regulator (Barone et al., 2016). CDK18 depletion causes a huge increase in endogenous DNA damage and inherited chromosomal abnormalities. Importantly, these phenotypes can be rescued in a CDK18 activity-dependent manner, suggesting that CDK18 substrate phosphorylation regulates the DDR. To reveal regulatory components of novel CDKs, such as the CDK18 signaling module, we will exploit probes and integrate them into a phosphoproteomic workflow to form a systems-based approach. This will reveal the mechanism(s) through which CDK18 maintains a 'healthy' genome.