Abstract
BackgroundThe Mitotic Spindle Assembly Checkpoint (MSAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.Principle FindingsWe have constructed and validated for the human MSAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the MSAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the “Dissociation” and the “Convey” model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.ConclusionOnly in the controlled case, our models show MSAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for MSAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.
Highlights
The growth of all organisms requires that the genome is accurately replicated and partitioned between two cellular progenies
Our simulations revealed that for Mitotic Spindle Assembly Checkpoint (MSAC) activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding
We developed a theoretical model of the human biochemical mitotic checkpoint at meta- to anaphase transition
Summary
The growth of all organisms requires that the genome is accurately replicated and partitioned between two cellular progenies. Eukaryotic cells have evolved a surveillance mechanism for DNA segregation, the MSAC This checkpoint blocks anaphase onset and prevents exit from mitosis until all chromosomes are properly attached and have aligned on the mitotic spindle. Designing a simplified model of radial symmetry, they observed that amplifying the signal through the release of a diffusible inhibitory complex can describe checkpoint function. Their model does not fully take into account the molecular complexity. A similar approach was presented by Sear et al [21] They investigated two mechanisms for MSAC in metazoan cells: one involves free diffusion and sequestration of cell cycle regulators requiring a two-stage signal amplification cascade.
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