Modeling the Budding Yeast Cell Cycle

Description of parameters

An upper or lower bound is given for those sensitive parameters that cannot be varied either 10 fold in either direction without violating our criteria for cell viability, which are described in our assay for robustness. Outside of these bounds, the simulation will yield an inviable cell and a diagnosis of inviability is given.

MASS

: growth rate

CLN3 – BCK2

 : Max. Cln3 activity

: Dosage of CLN3 gene

: Bck2 conc.

: MM constant

CLN2

: background synthesis of Cln2

: SBF-dependent synthesis of Cln2
upper bound: 5.7 fold up, otherwise telophase arrest

: degradation of Cln2
lower bound: 0.25 fold down, otherwise after the 6th division, Esp1=0.03<0.1.

CLB5

: background synthesis of Clb5

: MBF-dependent synthesis of Clb5

: background degradation of Clb5

: degradation of Clb5 by Cdc20

: Sic1 and Clb5 association to form an inactive trimer

: Sic1 and Clb5 dissociation

: Cdc6 and Clb5 association to form an inactive trimer

: Cdc6 and Clb5 dissociation

CLB2

: background synthesis of Clb2

: Mcm1-dependent synthesis of Clb2
upper bound: 8 fold up, otherwise telophase arrest
lower bound: 0.7 fold down , otherwise in the first mitosis, Esp1=0.084<0.1

: background degradation of Clb2

: degradation of Clb2 by Cdh1

: degradation of Clb2 by Cdc20
upper bound: 2 fold up, otherwise in the first mitosis, Esp1=0.06<0.1

: Sic1 and Clb2 association to form an inactive trimer

: Sic1 and Clb2 dissociation

: Cdc6 and Clb2 association to form an inactive trimer

: Cdc6 and Clb2 dissociation

SIC1

: background synthesis of Sic1

: Swi5-dependent synthesis of Sic1
upper bound: 2.8 fold up, otherwise in the first mitosis, Esp1=0.037<0.1

: background phosphorylation of Sic1

: phosphorylation of Sic1 by CDKs

: degradation of phosphorylated form of Sic1
lower bound: 0.18 fold down, otherwise in the first mitosis, Esp1=0.068<0.1

: dephosphorylation of Sic1 by Cdc14

: efficiency of Cln3 on Sic1 phosphorylation

: efficiency of Cln2 on Sic1 phosphorylation

: efficiency of Bck2 on Sic1 phosphorylation

: efficiency of Clb5 on Sic1 phosphorylation

: efficiency of Clb2 on Sic1 phosphorylation

: MM constant for Sic1 phosphorylation by CDKs.

CDC6

: background synthesis of Cdc6

: Swi5-dependent synthesis of Cdc6
upper bound: 2.8 fold up, otherwise in the first mitosis, Esp1=0.045 <0.1

: SBF-dependent synthesis of Cdc6

: background phosphorylation of Cdc6

: phosphorylation of Cdc6 by CDKs
lower bound: 0.13 fold down , otherwise at 3rd cycle, cell divides at mass>10

: degradation of phosphorylated form of Cdc6

: dephosphorylation of Cdc6 by Cdc14

: efficiency of Cln3 on Cdc6 phosphorylation

: efficiency of Cln2 on Cdc6 phosphorylation

: efficiency of Bck2 on Cdc6 phosphorylation

: efficiency of Clb5 on Cdc6 phosphorylation

: efficiency of Clb2 on Cdc6 phosphorylation

: MM constant for Cdc6 phosphorylation by CDKs.

SWI5

: background synthesis of Swi5

: Mcm1-dependent synthesis of Swi5
upper bound: 2 fold up, otherwise in the first mitosis, Esp1=0.03<0.1

: degradation of Swi5
lower bound: 0.18 fold down, otherwise at the 8th cycle, cell divides at mass>10

: activation of Swi5 by Cdc14

: inactivation of Swi5 by Clb2

IE

: activation of IE by Clb2 (phosphorylation)

: inactivation of IE (dephosphorylation)

: MM constant

: MM constant

CDC20

: background synthesis of Cdc20

:Mcm1-dependent synthesis of Cdc20
lower bound: 0.35 fold down, otherwise arrest at the 10th cycle

: degradation of Cdc20
upper bound: 2 fold up, otherwise not enough Cdc20 activated and Esp1 levels are low

: background activation of Cdc20

: activation of Cdc20 by IEP

: inactivation of cdc20 by Mad2

CDH1

: synthesis of Cdh1

: degradation of Cdh1

: background activation of Cdh1

: activation of Cdh1 by Cdc14 (dephosphorylation)
upper bound: 5.7 fold up, otherwise in the 1st mitosis, Esp1=0.078<0.1

: background inactivation of Cdh1

: inactivation of Cdh1 by the CDKs

: efficiency of Cln3 on Cdh1 activation

: efficiency of Cln2 on Cdh1 activation

: efficiency of Clb5 on Cdh1 activation

: efficiency of Clb2 on Cdh1 activation

: MM constant

: MM constant

CDC14 - NET1

: synthesis of Cdc14
upper bound: 2 fold up, otherwise G1 arrest
lower bound: 0.5 fold down, otherwise telophase arrest

: degradation of Cdc14
upper bound: 2 fold up, otherwise telophase arrest
lower bound: 0.5 fold down, otherwise G1 arrest

: synthesis of Net1
upper bound: 2 fold up, otherwise telophase arrest
lower bound: 0.13 fold down, otherwise in the 3rd cycle, cell divides at mass>10

: degradation of Net1
upper bound: 8 fold up, otherwise G1 arrest
lower bound: 0.35 fold down, otherwise telophase arrest

: background dephosphorylation of Net1

: dephosphorylation of Net1 by PPX
upper bound: 8 fold up, otherwise telophase arrest
lower bound: 0.5 fold down, otherwise at first mitosis, Esp1=0.076<0.1

: background phosphorylation of Net1

: phosphorylation of Net1 by Cdc15

: Cdc14 and Net1 association to form RENT

: Cdc14 and Net1P association to form RENTP

: Cdc14 and Net1 dissociation

: Cdc14 and Net1P dissociation

TEM1

: inactivation of Tem1 by Bub2

: activation of Tem1 by Let1

: MM constant

: MM constant

: Tem1 total

CDC15

: background activation of Cdc15 by inactive form of Tem1

: activation of Cdc15 by Tem1

: (=ka15p) activation of Cdc15 by Cdc14

: inactivation of Cdc15

: Total Cdc15

PPX

: synthesis of PPX
upper bound: 8 fold up, otherwise telophase arrest
lower bound: 0.5 fold down, otherwise at 1st mitosis, Esp1=0.07<0.1

: background degradation of PPX
upper bound: 2 fold up, otherwise at 1st mitosis, Esp1=0.078<0.1

: degradation of PPX by Cdc20
upper bound: 5.7 fold up, otherwise at 1st mitosis, Esp1=0.095<0.1

  : Pds1 inhibition of PPX degradation by Cdc20

: MM constant
upper bound: 5.7 fold up, otherwise at 1st mitosis, Esp1=0.095<0.1

PDS1 – ESP1

: background synthesis of Pds1

: SBF-dependent synthesis of Pds1

: Mcm1-dependent synthesis of Pds1
upper bound: 1.4 fold up, otherwise at 1st mitosis, Esp1=0.06<0.1

: background degradation of Pds1
upper bound: 4 fold up, otherwise Esp1 is high throughout the cell cycle

: degradation of Pds1 by Cdc20
lower bound: 0.7 fold down , otherwise at 1st mitosis, Esp1=0.06<0.1

: degradation of Pds1 by Cdh1

: Pds1 and Esp1 association to form inactive complex
lower bound: 0.13 fold down, otherwise Esp1 is high throughout the cycle

: Pds1 and Esp1 dissociation

: ESP1 total
upper bound: 1.4 fold up, otherwise Esp1 is high throughout the cycle
lower bound: 0.7 fold down, otherwise at 1st mitosis, Esp1=0.036<0.1

SBF

: activation of SBF
lower bound: 0.35 fold down, otherwise no bud and Esp1 is high throughout the cycle

: background inactivation of SBF
upper bound: 2.8 fold up, otherwise no bud and Esp1 is high throughout the cycle

  : inactivation of SBF by Clb2

: efficiency of SBF activation by Cln2

: efficiency of SBF activation by Cln3
lower bound: 0.25 fold down, otherwise no bud and Esp1 is high throughout the cycle

: efficiency of SBF activation by Clb5

: MM constant

: MM constant

MCM1

: activation of Mcm1 by Clb2
lower bound: 0.13 fold down, otherwise mass at 2nd division>10

: inactivation of Mcm1
upper bound: 8 fold up, otherwise mass at 2nd division>10

: MM constant

: MM constant

CONTROLS

ORI: monitoring of DNA synthesis:

, .

When ORI reaches 1, firing of origins of replication occurs, triggered by Clb5 and Clb2 ( , and )

BUD: monitoring of bud emergence:

, .

When BUD reaches 1, bud emerges, triggered by Cln3, Cln2 and Clb5 ( , , and )

SPN: monitoring of chromosome alignment on the mitotic spindle triggered by Clb2:

, , .

Threshold values

: exit from mitosis when Clb2 drops below this value

: ORI is reset to 0 when Clb2+Clb5 drops below this value