The enzyme Cdc14, which helps shut down the mitotic machinery, cycles in and out of the nucleolus. Manzoni et al. reveal how cells control the enzyme's oscillations so that it is available at the crucial time.
Cdc14 strips phosphates from proteins activated by cyclins and cyclin-dependent kinases (Cdks). Cells free Cdc14 from the nucleolus late in mitosis. Two interacting pathways orchestrate the process. The FEAR pathway spurs Cdc14's release at the beginning of anaphase. The MEN pathway ensures that the release continues, enabling Cdc14 to spread to the cytoplasm. Previous studies have shown that three kinases in these pathways are key: the polo-like kinase Cdc5, a cyclin–Cdk combo (Clb–Cdk), and Dbf2.
Manzoni et al. teased out the effects of each kinase in yeast cells and found what they call a two-hit mechanism. The first hit is Cdc5, which is essential for Cdc14 release. The second hit is either Dbf2 or the cyclin–Cdk combo. The results suggest that the cyclin in the pair can be Clb2 or Clb5.
The researchers hypothesize that Cdc5 teams up with cyclin–Cdk complexes to unleash Cdc14. The cyclins start breaking down around the beginning of anaphase, so Dbf2, part of the MEN pathway, steps in to maintain Cdc14 levels. Later in mitosis Cdc5 starts to degrade, and Cdc14 returns to confinement. Manzoni et al. found that nondegradable cyclins triggered oscillations in which Cdc14 continually shuttled in and out of the nucleolus. They suggest that there are benefits to linking control of Cdc14 to the cyclin–Cdk complexes that drive the cell cycle. That could allow cells to manage Cdc14's oscillations so that its levels rise and fall only once during each cycle.