Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models

Abstract

In eukaryotes, cyclin-dependent kinases (CDKs) are required for the onset of DNA replication and mitosis, and distinct CDK–cyclin complexes are activated sequentially throughout the cell cycle. It is widely thought that specific complexes are required to traverse a point of commitment to the cell cycle in G1, and to promote S-phase and mitosis, respectively. Thus, according to a popular model that has dominated the field for decades, the inherent specificity of distinct CDK–cyclin complexes for different substrates at each phase of the cell cycle generates the correct order and timing of events. However, the results from the knockouts of genes encoding cyclins and CDKs do not support this model. An alternative “quantitative” model, validated by much recent work, suggests that it is the overall level of CDK activity (with the opposing input of phosphatases) that determines the timing and order of S-phase and mitosis. We take this model further by suggesting that the subdivision of the cell cycle into discrete phases (G0, G1, S, G2, and M) is outdated and problematic. Instead, we revive the “continuum” model of the cell cycle and propose that a combination with the quantitative model better defines a conceptual framework for understanding cell cycle control.

A Mechanistic Model for Cell Cycle Control in Which CDKs Act as Switches of Disordered Protein Phase Separation

“…Furthermore, while affinity differences of CDK1-cyclin complexes for different substrates clearly exist [ 15 ], and could in theory generate different timing of substrate phosphorylation in the cell cycle, this would rely on CDK-cyclin activity being strongly rate-limiting in vivo, yet the system appears to behave more like a bistable switch. In such a system, the protein phosphatase activity is more important in determining the substrate phosphorylation state (see accompanying review, [ 19 ]). Thus, it seems unlikely that a sophisticated code of substrate recognition could explain how hundreds of targets get phosphorylated by CDK1 at mitotic entry, and has not yet been confirmed in vivo.…”

“…These conclusions are consistent with results obtained by other labs and in different systems, which elegantly demonstrated that no cyclin or CDK is indispensable, and instead, it is the overall kinase-to-phosphatase activity ratio that dictates in which phase of the cell cycle a cell is [ 22 , 23 ]. Thus, in the absence of CDK2, S-phase can be controlled by CDK1 [ 24 , 25 , 26 ], and if overall kinase activity is sufficiently high, CDK1 and cyclin B can be substituted by CDK2 and other cyclins to trigger entry into mitosis [ 27 , 28 ] (see also [ 19 ] in the same issue).…”

The Moso Bamboo D-Type Cell Cycle Protein Family: Genome Organization, Phylogeny, and Expression Patterns

“…For instance, in animal cells, CycBs play a major role in M phase entry [7], whereas CycDs are essential for re-entering cell progression in reaction to extracellular signals [8], and the S phase is accelerated by CycEs [9]. CycD/CDK (D-type cyclin) complexes are stimulated by mitogenic signals, including the gene expression process, complex formation, and migration into nuclei [10]. In animal cells, CDK4 and CDK6 form complexes that bind and phosphorylate the pRB (retinoblastoma protein and the fragment sequence in CycDs) and then inactivate and release the E2F, letting cells transition from the G1 phase into the S phase [11].…”