Modeling the Budding Yeast Cell Cycle


Basic mechanism

To understand the basic logic of the cell cycle, to a first approximation, we (and, independently, Kim Nasmyth) have envisioned that the cell cycle in budding yeast is an alternation between two self-maintaining stable steady states (G1 and S/G2/M). The Start transition carries a cell from G1 to S/G2/M, and the Finish transition from M back to G1 (Nasmyth, 1996, Tyson et al., 1995, Tyson et al., 2001).

The two self-maintaining steady states arise primarily from the mutual antagonism between B-type cyclins (Clb1-6, in association with Cdc28) and the G1 stabilizers (Cdh1, Sic1 and Cdc6). Cdh1/APC degrades the Clbs, whereas Sic1 and Cdc6, referred to together as the CKIs, stochiometrically inhibit Cdc28/Clb complexes. Clb-kinases, on the other hand, can inactivate Cdh1 and destabilize CKIs. Since Clb-kinases and the G1 stabilizers mutually inhibit each other, these two classes of proteins cannot coexist.In the G1 state, Clb-kinase activities are low because Clb synthesis processes are turned OFF, their degradation by APC/Cdh1 is ON, and their inhibitors, the CKIs, are abundant. The reverse is true in the S/G2/M phase. Furthermore, it is important to note that:

  1. The transitions between these two alternative steady states (G1 and S/G2/M) requires helper molecules (detailed in Chen et al., 2000).

  2. The Start transition is facilitated by Cln-kinases (Cln1-3/Cdc28 complexes) that can phosphorylate and inactivate CKI and Cdh1, but are not themselves opposed by CKI and Cdh1. This transition is driven by cell growth. When the small daughter cell has grown to a critical size and Cln-kinase activities have reached a critical level, CKI and Cdh1 are inactivated, Clb-kinase activities increase, a bud emerges, DNA replication commences and spindle pole is duplicated. (The mother cell executes Start soon after birth because it has already attained the critical size.) The rising activity of Clb-kinases turns off Cln synthesis, causing Cln-kinase activities to drop in preparation for the Finish transition.

  3. The Finish transition is facilitated by Cdc20, which is activated indirectly by Clb-kinases. When the spindle assembly checkpoint is lifted (DNA synthesis is complete and chromosomes are aligned on the metaphase plate), Cdc20 is activated, sister chromatids are separated, and Clbs are partially degraded. Cdc20 also initiates the activation of the phosphatase Cdc14, which reverses the inhibitory effects of Clb-kinases on Cdh1 and CKIs, allowing the latter two to overpower the Clb-kinases and extinguish their activities. As Clb-kinase activities drop after Finish, Cdc20 activity also disappears, preparing the cell for the subsequent Start transition.