Mitotic kinase oscillation governs the latching of cell cycle switches

In 1996, Kim Nasmyth¹ proposed that the eukaryotic cell cycle is an alternating sequence of transitions from G₁ to S-G₂-M and back again. These two phases correlate to high activity of cyclin-dependent kinases (CDKs) that trigger S-G₂-M events and CDK antagonists that stabilize G₁ phase. We associated these "alternative phases" with the coexistence of two stable steady states of the biochemical reactions among CDKs and their antagonists.^2,3 Transitions between these steady states (G₁-to-S and M-to-G₁) are driven by "helper" proteins. The fact that the transitions are irreversible is guaranteed by a "latching" property of the molecular switches, as we have argued in previous publications.^4,5 Here, we show that if the latch is broken, then the biochemical reactions can swing back-and-forth across the transitions; either G₁-S-G₁-S … (periodic DNA replication without mitosis or cell division) or M-(G₁)-M-(G₁) … (periodic Cdc14 release, without fully exiting mitosis). Using mathematical modeling of the molecular control circuit in budding yeast, we provide a fresh account of aberrant cell cycles in mutant strains: endoreplication in the clb1-5Δ strain⁶ and periodic release and resequestration of Cdc14 (an "exit" phosphatase) in the CLB2kdΔ strain.^7,8 In our opinion, these "endocycles" are not autonomous oscillatory modules that must be entrained by the CDK oscillator^6,7 but rather inadvertent and deleterious oscillations that are normally suppressed by the CDK latching-gate mechanism.⁸.