Qualitative and quantitative Cdk control of the budding yeast cell cycle

Abstract

Timely and ordered progression through the cell cycle is crucial for error-free proliferation of cells. In eukaryotes, cell division cycle is controlled by the master regulator cyclin-cyclin dependent kinase (Cdk) complexes. However, it is still unclear how cyclin-Cdk complexes ensure the order in the cell cycle so that DNA replication in S phase always precedes chromosome segregation in mitosis.

Two models have been put forward to explain cell cycle ordering by cyclin-Cdk complexes. The qualitative model suggests that distinct substrate specificities of the different cyclins at successive cell cycle stages order substrate phosphorylation. In contrast, the quantitative model for Cdk control of the cell cycle suggests that the overall gradual increase in Cdk activity from G1 to mitosis orders cell cycle progression. In line with the quantitative model, a single cyclin-Cdk complex is sufficient to order the fission yeast cell cycle. However, the relative contributions of qualitative and quantitative Cdk control in other organisms is incompletely understood.

In this project, I investigate cyclin specificity and redundancy in the budding yeast S. cerevisiae, which encodes three G1 (Cln1-3), two S (Clb5 and Clb6) and four G2/M (Clb1-4) cyclins that are orthologous to those found in many metazoans, including humans. With an aim to identify the minimal set of cyclins required to drive the ordered cell cycle progression in budding yeast, I have removed seven of the nine cyclins, establishing a strain harbouring one G1 cyclin, Cln2, and a mitotic cyclin, Clb2, that is expressed from an S phase cyclin CLB5 promoter in addition to its own promoter. In this strain, expressing a third copy of Clb2 under control of CLN2 promoter is sufficient to order DNA replication and chromosome segregation in the absence of Cln2. However, these cells cannot polarise or form buds. My findings indicate that the budding yeast G1 cyclin Cln2 has evolved to carry unique crucial functions to couple cell cycle progression to morphogenetic events.