Modeling the Budding Yeast Cell Cycle

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• Checkpoint proteins
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Checkpoint proteins

Wild type cells arrest in mitosis in response to spindle damage (Taylor, 1999; Hoyt, 2000) when treated with nocodazole or benomyl. The genes involved in the surveillance mechanism are: MAD1-3 (Li & Murray, 1991) and BUB1-3 (Hoyt et al., 1991). ("MAD" stands for "Mitotic Arrest Deficient" and "BUB" for "Budding Uninhibited by Benomyl" respectively, which describe mutant phenotypes when the genes are not functional.) These genes are non-essential; deletions of MAD2 and BUB2 behave like wild-type (Fraschini et al., 1999; Alexandru et al., 1999, Fig. 4). In the model Mad2 controls Cdc20 activation (Alexandru et al., 1999), and Bub2 regulates Cdh1 activation (Tavormina & Burke, 1998; Alexandru et al., 1999).

Function and level: Mad2 and Bub2 are involved in spindle assembly checkpoint but respond to spindle damage via two different, interacting pathways (Alexandru et al., 1999; Li, 1999; Fraschini et al., 1999; Gardner & Burke, 2000).

• Mad2: spindle assembly checkpoint protein.
  
  • Mad2 localizes to the unattached kinetochore (Chen et al., 1996; Li et al., 1997; Krishnan et al., 2000) and sequester Cdc20 and preventing Cdc20 from activating the APC (Hwang et al., 1998; Elledge, 1998).
  • In a mad2 in nocodazole, the checkpoint is defective, Cdc20 can activate. After long incubation (~300 min), some mechanism triggers Clb2 degradation and cells eventually exit mitosis (Alexandru et al., 1999).
  • Mad2 level is constant throughout the cell cycle (Chen et al., 1999).


• Bub2: spindle assembly checkpoint protein.
  
  Bub2 responds to abnormal spindle structure rather than unattached kinetochores (Fraschini et al., 1999).
  Bub2 interacts with Bfa1, another checkpoint protein (Fraschini et al., 1999; Li, 1999; Pereira et al., 2000; Lee et al., 2001b; Hu et al., 2001). Their activity is monitored by spindle orientation (Geymonat et al., 2003).
  • Bfa1/Bub2 located on the spindle pole body along with the GTPase Tem1, keeping it inactive (Fraschini et al., 1999; Pereira et al., 2000).
  • Bub2/Bfa1 complex ensures a proper chromosome segragation before the cell can exit mitosis. Both proteins are involved in the Mitotic Exit Network.
  • In bub2 in nocodazole, Mad2 is functional keeping Cdc20 inactive. After long incubation, the cells eventually exit mitosis with unseparated sister chromatids and a second bud (Hoyt et al., 1991; Alexandru et al., 1999).
  • Bub2 level does not fluctuate during the cell cycle (Fraschini et al., 1999). In anaphase, when its activity is shut off, Bub2 is located in the bud (Pereira et al., 2000).