A quantitative model for cyclin-dependent kinase control of the cell cycle: revisited

Abstract

The eukaryotic cell division cycle encompasses an ordered series of events. Chromosomal DNA is replicated during S phase of the cell cycle before being distributed to daughter cells in mitosis. Both S phase and mitosis in turn consist of an intricately ordered sequence of molecular events. How cell cycle ordering is achieved, to promote healthy cell proliferation and avert insults on genomic integrity, has been a theme of Paul Nurse's research. To explain a key aspect of cell cycle ordering, sequential S phase and mitosis, Stern & Nurse proposed 'A quantitative model for cdc2 control of S phase and mitosis in fission yeast'. In this model, S phase and mitosis are ordered by their dependence on increasing levels of cyclin-dependent kinase (Cdk) activity. Alternative mechanisms for ordering have been proposed that rely on checkpoint controls or on sequential waves of cyclins with distinct substrate specificities. Here, we review these ideas in the light of experimental evidence that has meanwhile accumulated. Quantitative Cdk control emerges as the basis for cell cycle ordering, fine-tuned by cyclin specificity and checkpoints. We propose a molecular explanation for quantitative Cdk control, based on thresholds imposed by Cdk-counteracting phosphatases, and discuss its implications.

Figure 1.

A model in which cell cycle ordering is due to a dependency of events. For example, mitosis (nuclear division) is dependent on the completion of S phase (DNA synthesis). Cells arrest before mitosis if they are deficient in a number of cell division cycle (cdc) genes, including cdc8 and cdc21—encoding thymidylate kinase and thymidylate synthetase required for nucleotide synthesis—and cdc9 and cdc17—encoding DNA ligase I and the catalytic subunit of DNA polymerase α, required for DNA replication. This dependency of events suggested that causalities order cell cycle transitions, which later were found to be enforced by checkpoints or surveillance mechanism. Reproduced with permission from Hartwell [20]. Copyright © The Rockefeller University Press.

Figure 2.

A model for how cyclin specificity orders S phase and mitosis in budding yeast. In this model, G1 and S-phase cyclins (Cln1,2 and Clb5,6) promote S phase, while mitosis is triggered by the mitotic cyclins Clb1,2. G1 cyclins and mitotic cyclins maintain their own activity, respectively, while mitotic cyclins repress G1 cyclins. Reproduced with permission from Amon et al. [38]. Copyright © Elsevier.

Figure 3.

A quantitative model for ordering S phase and mitosis in fission yeast. A single source of Cdk activity (Cdc13/Cdc2) is sufficient for ordering sequential S phase and mitosis. S phase is triggered by an intermediate level of Cdk activity, while mitosis depends on a higher kinase activity level. Reprinted with permission from Stern & Nurse [6]. Copyright © Elsevier.

Figure 4.

A kinase/phosphatase ratio model for ordering cell cycle progression. (a) Sequential phosphorylation or dephosphorylation events are the consequence of substrates responding to distinct thresholds of the changing Cdk to Cdk-counteracting phosphatase ratio. S-phase substrates are efficiently phosphorylated by low levels of Cdk even in the presence of Cdk-counteracting phosphatases. Phosphorylation of mitotic substrates awaits higher Cdk activity levels and phosphatase downregulation. Note that little is still known about the regulation of Cdk counteracting phosphatases. The depicted graph is hypothetical, inspired by what is known about budding yeast Cdc14, fission yeast Clp1 and vertebrate PP2A-B55δ [92,99,100]. (b) An example of ordered Cdk substrate dephosphorylation during budding yeast mitotic exit. Biochemical evidence shows that the Cdk-counteracting phosphatase Cdc14 targets early dephosphorylated substrates, e.g. Fin1, Ask1 and Sli15, with greater catalytic efficiency and causes their dephosphorylation even in the presence of persisting Cdk activity. Late substrates, involved in spindle disassembly and return of the cell cycle to G1, e.g. Orc6 and Cdh1, are dephosphorylated with lower catalytic efficiency, awaiting a greater Cdc14-to-Cdk ratio [101].