Modeling the Budding Yeast Cell Cycle

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• Introduction
• Rationale
• Budding yeast biology
• Components & function
• Cell cycle progression
• Basic mechanism
• Major improvement
• Overview
• Wiring diagram
• Description
• Justification
• Cyclins
• Cdc20
• Cdh1
• Cdc14 activation
• Mitotic Exit Network
• Pds1/Esp1 interaction
• CKI
• Checkpoint proteins
• Formulation
• Simulation
• Conclusions
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• Parameters
• Problems
• Predictions
• Robustness
• Mutants
• List of Mutants
• WT in glucose
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• Cln
• Bck2
• cln1 cln2 cln3
• Clb5 Clb6
• Clb1 Clb2
• Sic1
• Cdc6
• Cdh1
• Cdc20
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Introduction

Biology of the budding yeast:

The cell cycle is the succession of events whereby a cell grows and divides into two daughter cells that each contain the information and machinery necessary to repeat the process. Between one cell division and the next, all essential components of the cell must be duplicated. The most important component is the genetic material (DNA molecules present in chromosomes), which must be accurately replicated and the two copies carefully segregated to the two daughter cells. The processes of DNA replication and sister chromatid separation occur in temporally distinct phases of the eukaryotic cell cycle. These are known as S-phase (DNA synthesis) and M-phase (mitosis),  In general, S and M phases separated by two gaps, known as G1 and G2.

The unicellular budding yeast, Saccharomyces cerevisiae, is a model system to study cell cycle regulation.  As a yeast cell progresses through the cell cycle, it halts at two major checkpoints:

• the G1 checkpoint:  If DNA damage is detected, mating pheromone is present, or the cell has not reached the critical size, the cell arrests in G1 and is unable to undergo the Start transition which commits the cell to a new round of DNA synthesis and mitosis.
• the spindle assembly checkpoint:  If DNA damage is detected, DNA is not replicated completely, or chromosomes are not aligned on the metaphase plate, the cell arrests in metaphase and is unable to undergo the Finish transition, whereby sister chromatids are separated and the cell divides.

These checkpoints are enforced by the Cdk/cyclin complexes, a family of protein kinases.  The catalytic subunit of these complexes, the cyclin-dependent kinase (Cdk), is only active when combined with a regulatory cyclin subunit.  In budding yeast, there is only one Cdk (called Cdc28); and nine different cyclins (Cln1-3, Clb1-6). Depending on the cyclin partner, Cdc28/cyclin dimers accomplish specific and different tasks.  Proper progression through the cell cycle requires the successive activation and inactivation of these Cdc28/cyclin dimers. There are several different mechanisms for regulating Cdc28 activity in the cell, namely:

• through the synthesis of cyclins by various transcription factors (SBF, MBF and Mcm1).
• through the degradation of cyclins (promoted by Cdc20/APC, Cdh1/APC, and Grr1/SCF).
• through association with stoichiometric CDK inhibitors (Sic1 and Cdc6, and Far1).
• through phosphorylation and dephosphorylation of Cdc28 by Swe1 and Mih1.

The regulatory proteins that control the activities of Cdc28 and ensure the proper progression of cell cycle events are listed below.