Understanding the Regulation and Function of CDK8 Using Saccharomyces Cerevisiae

Abstract

Cdk8 is a conserved protein kinase and a member of the Mediator transcription co-activator complex. Accumulating evidence highlights CDK8 as an oncogene in colorectal cancer, emphasizing the need to understand its function and regulation. Notably, CDK8 amplification or overexpression is observed in approximately 60% of colon cancer tumours and has been detected in melanoma, leukemia, as well as breast, pancreatic, and prostate cancer. Collectively, this evidence has stimulated efforts to develop Cdk8 inhibitors for cancer therapy. Despite a growing interest to target Cdk8 for anti-cancer treatment we have limited information about Cdk8 regulation, a knowledge gap that may complicate efforts to block its activity. To understand the function and regulation of Cdk8, I used the budding yeast model system and leveraged disease-associated variability and recent insight from structural and biochemical analyses. Specifically, using information from primary cancer studies and ClinVar I identified a cluster of CDK8 missense mutations that localize to the kinase ATP binding pocket and sites of interaction with proteins known to regulate Cdk8 kinase activity, that affect CDK8 function. Careful examination of these mutants suggests the existence of a feedback mechanism that regulates Cdk8 protein and mRNA levels. In addition, my work also showed that the interaction between Cdk8 and Med12 regulates CDK8 function in a condition-specific manner. Collectively, this research sheds light on the function and regulation of Cdk8, work that will inform the development of targeted therapies and enhance our understanding of the mechanisms by which Cdk8 contributes to cancer development.