Modeling the Budding Yeast Cell Cycle

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Change of parameters: kbub2l=0, ksspn=0, init BUB2=0.

Arrest: Metaphase arrest.

Experimental results: Hoyt: bub2∆ cells lose viability after many hours in nocodazole. They exit mitosis and re-bud without segregating their chromosomes.
Alexandru: Figs. 1C and 6A, exit of mitosis at t>300 min.

Comments: Problem for the model. This mutant is predicted to be metaphase arrested, because the MAD2 pathway is still intact, which keeps Clb2 and Clb5 kinases active and Pds1 level high. Although Cdc15/MEN is activated, Cdc14 is not fully released (due to high Pds1), and Cdh1 is not activated (due to high Clb2 and Clb5 kinase activities).

If we adjust parameters in the MEN pathway to simulate the observed phenotype of bub2∆ in nocodazole, then we upset simulations of other mutants, e.g., cdc20∆ pds1∆ to arrest in telophase, cdc20∆ clb5∆ to arrest in M phase, pds1∆ to arrest in nocodazole, and GAL-PDS1-db∆ to delay cytokinesis. (All of them have less severe problem in exiting from mitosis than bub2∆ in nocodazole.)

The failure to model the behavior of bub2∆ in nocodazole suggests that there is some cross-talk from the BUB2 pathway to the MAD2 pathway: perhaps signals from the BUB2 pathway somehow dampen the inhibition of Cdc20 by Mad2. For example, Cdc5 might phosphorylate and partially activate Cdc20/APC, when Bub2 is deleted. Partially activated Cdc20/APC might eventually target enough Pds1, Clb5 and Clb2 for degradation that bub2∆ in nocodazole would exit from mitosis and die.