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Novak2022 - Mitotic kinase oscillation

ABSTRACT: Bela Novak & John J. Tyson. Mitotic kinase oscillation governs the latching of cell cycle switches. Current Biology 32, 12 (2022). 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. 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. 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 strain 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 but rather inadvertent and deleterious oscillations that are normally suppressed by the CDK latching-gate mechanism.

SUBMITTER: Mikal Daou

PROVIDER: BIOMD0000001058 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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Project description:To achieve faithful replication of the genome once in each cell cycle, re-initiation of S-phase is prevented in G2 and origins are restricted from re-firing within S-phase. We have investigated the block to re-replication during G2 in fission yeast. The DNA synthesis that occurs when G2/M cyclin dependent kinase (CDK) activity is depleted has been assumed to be repeated rounds of S-phase without mitosis but this has not been demonstrated to be the case. In a normal mitotic S-phase, the genome is uniformly replicated with no areas amplified relative to other regions, so there is an equal copy number of each portion of the genome. To determine whether equal rounds of replication or local amplification occurred in the cdc13 s/o strain we assayed genomic DNA from cells which had increased their DNA content to 16C-32C. Using microarrays, we measured the relative DNA content across the genome, using DNA from control G1-arrested cells as a reference. This experiment revealed that replication was essentially equal across the genome, with no region becoming significantly amplified to a higher copy number than any other. Since the genome was found to be essentially evenly replicated as would be expected if each round of replication corresponded to a normal S-phase, we investigated whether this was the result of a normal replication program at the level of origin firing. We asked whether S-phase origins are used to reduplicate the genome, and whether origins are used with the same efficiency as in wild type cells. We identified the origins utilized in the first endoreduplication cycle of cdc13 s/o using microarray analyses of cells treated with 11 mM HU. Samples were taken at 5 hours when most cells of the culture not treated with HU had undergone a doubling in DNA content. A total of 799 origins were identified, a number roughly similar to the 904 identified in a normal S-phase. We show here that on G2/M CDK depletion in G2, repeated S-phases are induced. Mostly normal mitotic S-phase origins were utilized although at different efficiencies, and replication was essentially equal across the genome. We conclude that CDK inhibits re-initiation of S-phase during G2, and if G2/M CDK is depleted replication results from induction of a largely normal S-phase program with only small differences in origin usage and efficiency.

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Novak2022 - Mitotic kinase oscillation

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