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Using default constraints of the spindle assembly checkpoint to estimate the associated chemical rates.

Dao Duc K, Holcman D - BMC Biophys (2012)

Bottom Line: Our purpose is to use these opposed constraints to estimate the associated chemical rates.We compute the probability for no APC/C activation before time t, the distribution of Cdc20 at equilibrium and the mean time to complete APC/C activation after all chromosomes are attached.By studying Cdc20 inhibition and the activation time, we obtain a range for the main chemical reaction rates regulating the spindle assembly checkpoint and transition to anaphase.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Biology (IBENS), Group of Computational Biology and Applied Mathematics, Ecole Normale Supérieure, 46 rue d'Ulm 75005 Paris, France. holcman@ens.fr.

ABSTRACT

Unlabelled: :

Background: Default activation of the spindle assembly checkpoint provides severe constraints on the underlying biochemical activation rates: on one hand, the cell cannot divide before all chromosomes are aligned, but on the other hand, when they are ready, the separation is quite fast, lasting a few minutes. Our purpose is to use these opposed constraints to estimate the associated chemical rates.

Results: To analyze the above constraints, we develop a markovian model to describe the dynamics of Cdc20 molecules. We compute the probability for no APC/C activation before time t, the distribution of Cdc20 at equilibrium and the mean time to complete APC/C activation after all chromosomes are attached.

Conclusions: By studying Cdc20 inhibition and the activation time, we obtain a range for the main chemical reaction rates regulating the spindle assembly checkpoint and transition to anaphase.

No MeSH data available.


Related in: MedlinePlus

A schematic view of the spindle assembly checkpoint and anaphase. A: Before all chromosomes are all attached, the mitotic checkpoint complex inhibits the Cdc20 molecules binding with APC/C to prevent premature separation of sister chromatids. This signal ubiquitylates Cdc20. B: When all chromosomes are properly attached, the inhibiting signal is shut down. C and D: Activation of APC/C triggers the separation of the chromatids and ultimately the anaphase.
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Figure 1: A schematic view of the spindle assembly checkpoint and anaphase. A: Before all chromosomes are all attached, the mitotic checkpoint complex inhibits the Cdc20 molecules binding with APC/C to prevent premature separation of sister chromatids. This signal ubiquitylates Cdc20. B: When all chromosomes are properly attached, the inhibiting signal is shut down. C and D: Activation of APC/C triggers the separation of the chromatids and ultimately the anaphase.

Mentions: We describe here the time evolution of the joint probability distribution of Cdc20 molecules and of APC/C complex activation, the later being responsible for the chromosome separation. In this model, APC/C is located on the chromosomes (figure 1), and is a target of the Cdc20 molecule, although there are some conflicting evidences that APC/C is located on the kinetochores [21]. This assumption can affect the binding rate, but does not impact the construction of our model. For a cell containing N chromosomes, the targets of the Cdc20 molecules are the N associated kinetochores, containing the APC/C complexes. When a Cdc20 molecule reaches a kinetochore, it activates the APC/C complex and this can trigger a cascade of reactions (detailed in the background section) leading to the separation of the sister chromatids. The goal of the spindle assembly checkpoint signal is to prevent this activation of APC/C by Cdc20, when at least one of the chromosomes is not properly attached to the microtubules responsible for the chromatids migration. The spindle assembly checkpoint signal consists in the production of proteins such as Mad2, BubR1 and Mad3 [4], generated by unattached kinetochores. These proteins diffuse in large quantity in the cell to inhibit the APC/C binding by Cdc20 molecules. Indeed, these proteins form with Cdc20 a complex called mitotic checkpoint complex (MCC). Similar complexes can be found in yeast, in which a BubR1-related Mad3 protein might inhibit Cdc20 as a pseudo-substrate [22-24]. The formation of this complex results in Cdc20 ubiquitylation, which prevents APC/C activation. In our model, MCC will represent the complex of inhibitory proteins before it binds Cdc20, in contrast with the usual terminology where MCC includes Cdc20. Cdc20 molecules are produced from the dissociation of a complex [25], which could be a subcomplex of Mad2 and Cdc20 resulting from MCC:Cdc20 disassembly, promoted by p31 [26]. In summary, the above chemical reactions can be summarized as


Using default constraints of the spindle assembly checkpoint to estimate the associated chemical rates.

Dao Duc K, Holcman D - BMC Biophys (2012)

A schematic view of the spindle assembly checkpoint and anaphase. A: Before all chromosomes are all attached, the mitotic checkpoint complex inhibits the Cdc20 molecules binding with APC/C to prevent premature separation of sister chromatids. This signal ubiquitylates Cdc20. B: When all chromosomes are properly attached, the inhibiting signal is shut down. C and D: Activation of APC/C triggers the separation of the chromatids and ultimately the anaphase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368725&req=5

Figure 1: A schematic view of the spindle assembly checkpoint and anaphase. A: Before all chromosomes are all attached, the mitotic checkpoint complex inhibits the Cdc20 molecules binding with APC/C to prevent premature separation of sister chromatids. This signal ubiquitylates Cdc20. B: When all chromosomes are properly attached, the inhibiting signal is shut down. C and D: Activation of APC/C triggers the separation of the chromatids and ultimately the anaphase.
Mentions: We describe here the time evolution of the joint probability distribution of Cdc20 molecules and of APC/C complex activation, the later being responsible for the chromosome separation. In this model, APC/C is located on the chromosomes (figure 1), and is a target of the Cdc20 molecule, although there are some conflicting evidences that APC/C is located on the kinetochores [21]. This assumption can affect the binding rate, but does not impact the construction of our model. For a cell containing N chromosomes, the targets of the Cdc20 molecules are the N associated kinetochores, containing the APC/C complexes. When a Cdc20 molecule reaches a kinetochore, it activates the APC/C complex and this can trigger a cascade of reactions (detailed in the background section) leading to the separation of the sister chromatids. The goal of the spindle assembly checkpoint signal is to prevent this activation of APC/C by Cdc20, when at least one of the chromosomes is not properly attached to the microtubules responsible for the chromatids migration. The spindle assembly checkpoint signal consists in the production of proteins such as Mad2, BubR1 and Mad3 [4], generated by unattached kinetochores. These proteins diffuse in large quantity in the cell to inhibit the APC/C binding by Cdc20 molecules. Indeed, these proteins form with Cdc20 a complex called mitotic checkpoint complex (MCC). Similar complexes can be found in yeast, in which a BubR1-related Mad3 protein might inhibit Cdc20 as a pseudo-substrate [22-24]. The formation of this complex results in Cdc20 ubiquitylation, which prevents APC/C activation. In our model, MCC will represent the complex of inhibitory proteins before it binds Cdc20, in contrast with the usual terminology where MCC includes Cdc20. Cdc20 molecules are produced from the dissociation of a complex [25], which could be a subcomplex of Mad2 and Cdc20 resulting from MCC:Cdc20 disassembly, promoted by p31 [26]. In summary, the above chemical reactions can be summarized as

Bottom Line: Our purpose is to use these opposed constraints to estimate the associated chemical rates.We compute the probability for no APC/C activation before time t, the distribution of Cdc20 at equilibrium and the mean time to complete APC/C activation after all chromosomes are attached.By studying Cdc20 inhibition and the activation time, we obtain a range for the main chemical reaction rates regulating the spindle assembly checkpoint and transition to anaphase.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Biology (IBENS), Group of Computational Biology and Applied Mathematics, Ecole Normale Supérieure, 46 rue d'Ulm 75005 Paris, France. holcman@ens.fr.

ABSTRACT

Unlabelled: :

Background: Default activation of the spindle assembly checkpoint provides severe constraints on the underlying biochemical activation rates: on one hand, the cell cannot divide before all chromosomes are aligned, but on the other hand, when they are ready, the separation is quite fast, lasting a few minutes. Our purpose is to use these opposed constraints to estimate the associated chemical rates.

Results: To analyze the above constraints, we develop a markovian model to describe the dynamics of Cdc20 molecules. We compute the probability for no APC/C activation before time t, the distribution of Cdc20 at equilibrium and the mean time to complete APC/C activation after all chromosomes are attached.

Conclusions: By studying Cdc20 inhibition and the activation time, we obtain a range for the main chemical reaction rates regulating the spindle assembly checkpoint and transition to anaphase.

No MeSH data available.


Related in: MedlinePlus