Curran, Joseph Francis William; (2024) The role of the CKS protein Suc1 in cell cycle control. Doctoral thesis (Ph.D), UCL (University College London).

Text JCurran_Final_Thesis_v3.5_postcorrections.pdf - Accepted Version Access restricted to UCL open access staff until 1 October 2025. Download (29MB)

Abstract

Cyclin-Dependent Kinase Subunit (CKS) proteins are highly conserved, essential proteins, that bind to Cyclin-Dependent Kinases (CDKs), the master regulators of the eukaryotic cell cycle. A diverse range of phenotypes and molecular functions have been ascribed to these CKS proteins, yet despite being discovered as Suc1 in fission yeast nearly 40 years ago, a clear understanding of their role in cell cycle control remains lacking. I have performed a systematic analysis of the sole CKS protein, Suc1, in the fission yeast Schizosaccharomyces pombe. I utilised a novel temperature-sensitive allele to ablate Suc1 function in vivo and demonstrated roles at the G1/S transition, the G2/M transition, and in the execution of mitosis. Suc1 is required to increase the effective CDK activity of the S CDK complex in S phase ensuring the timely onset of DNA replication. At the G2/M transition, Suc1 is required for the activation of CDK via tyrosine dephosphorylation, regulating the kinetics of CDK activation and CDK activity levels in mitosis. Subsequently during mitosis, Suc1 is also required to target a subset of CDK sites for phosphorylation directly, particularly enhancing the phosphorylation of non-canonical CDK sites. I have defined and characterised this non-canonical CDK phosphorylation in vivo. Suc1-dependent substrates are enriched on multiply phosphorylated proteins, which conform to a previously proposed set of phospho-site priming criteria. However, these criteria account for only half of the most Suc1-dependent CDK sites. I therefore propose that the CKS priming criteria are incompletely understood, and that Suc1 stabilises CDK-substrate interactions via multiple modes. My work demonstrates that the individual phenotypes that have been reported previously can be recapitulated in one system in vivo, indicating that CKS proteins perform a complex role at multiple stages of the cell cycle. As such, I propose that CKS proteins should be considered a core component of Cyclin CDK complexes.

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