Core control principles of the eukaryotic cell cycle

Abstract

Cyclin-dependent kinases (CDKs) lie at the heart of eukaryotic cell cycle control, with different cyclin–CDK complexes initiating DNA replication (S-CDKs) and mitosis (M-CDKs)1,2. However, the principles on which cyclin–CDK complexes organize the temporal order of cell cycle events are contentious3. One model proposes that S-CDKs and M-CDKs are functionally specialized, with substantially different substrate specificities to execute different cell cycle events4–6. A second model proposes that S-CDKs and M-CDKs are redundant with each other, with both acting as sources of overall CDK activity7,8. In this model, increasing CDK activity, rather than CDK substrate specificity, orders cell cycle events9,10. Here we reconcile these two views of core cell cycle control. Using phosphoproteomic assays of in vivo CDK activity in fission yeast, we find that S-CDK and M-CDK substrate specificities are remarkably similar, showing that S-CDKs and M-CDKs are not completely specialized for S phase and mitosis alone. Normally, S-CDK cannot drive mitosis but can do so when protein phosphatase 1 is removed from the centrosome. Thus, increasing S-CDK activity in vivo is sufficient to overcome substrate specificity differences between S-CDK and M-CDK, and allows S-CDK to carry out M-CDK function. Therefore, we unite the two opposing views of cell cycle control, showing that the core cell cycle engine is largely based on a quantitative increase in CDK activity through the cell cycle, combined with minor and surmountable qualitative differences in catalytic specialization of S-CDKs and M-CDKs.

A quantitative and spatial analysis of cell cycle regulators during the fission yeast cycle

“…We conclude that this level of cyclin is sufficient to generate enough CDK activity to undergo mitosis but is restrained by the Cdc25/Wee1 regulatory loop until late in G2. The difference in Cdc13 concentration from mid-G2 to mitotic onset is about one-third, which could correspond to a “CDK buffer zone,” where cells undergo mitosis with a higher level of CDK activity than is strictly necessary for the completion of mitosis ( 17 , 49 ).…”

Plasmodium falciparum CRK4 links early mitotic events to the onset of S-phase during schizogony

“…2; S1D, S6). In analogy to canonical cell cycle kinases (Basu et al, 2022; Coudreuse and Nurse, 2010; Zegerman, 2015), Pf CRK4 activity is likely altered during parts of the nuclear cycle to allow for genome segregation and licensing of origins (Fig. 4D).…”

“…In other eukaryotes, cyclins and cyclin-dependent kinases (CDKs) drive the timely progression through the cell cycle (Basu et al, 2022; Malumbres, 2014). While no canonical G1, S- and M-phase cyclins could be identified (Robbins et al, 2017; Roques et al, 2015), the P. falciparum genome harbors CDK-like kinases and several related kinases, such as the cdc2-related kinase 4 ( Pf CRK4) (Doerig et al, 2002).…”

A Journey to the Core of the Plant Cell Cycle

“…S and M are separated by the pre-replicative G1 and the post-replicative G2 phases. Progression through S and M is dictated by the activity of cyclin-dependent kinases (CDKs)/cyclin complexes, which is regulated mainly at the quantitative level [ 1 ]. CDK activity also depends on the nature of cyclins and their availability, the presence of CDK inhibitors, and the activation/inhibition of the CDK moiety by protein phosphorylation and phosphatase balance.…”

“…In addition, there are other cyclic events coordinated with those occurring throughout these phases, such as the CDK/cyclin activity peaks, frequently in mid/late G1 and late G2, cytokinesis, centromere maturation, chromatin remodeling, among others. All of them are highly regulated to function in an unidirectional manner [ 1 , 2 ], as a consequence of several redundant or complementary pathways, e.g., gene expression, subcellular localization, post-translational modifications or targeted proteolysis. In the case of plants, the cell cycle is coordinated with morphogenesis by the direct interaction of cell cycle regulators with plant-specific cell fate pathways.…”