Evaluating putative mechanisms of the mitotic spindle checkpoint

Abstract

The mitotic spindle checkpoint halts the cell cycle until all chromosomes are attached to the mitotic spindles. Evidence suggests that the checkpoint prevents cell-cycle progression by inhibiting the activity of the APC-Cdc20 complex, but the precise mechanism underlying this inhibition is not yet known. Here, we use mathematical modeling to compare several mechanisms that could account for this inhibition. We describe the interplay between the capacities to strongly inhibit cell-cycle progression before spindle attachment on one hand and to rapidly resume cell-cycle progression once the last kinetochore is attached on the other hand. We find that inhibition that is restricted to the kinetochore region is not sufficient for supporting both requirements when realistic diffusion constants are considered. A mechanism that amplifies the checkpoint signal through autocatalyzed inhibition is also insufficient. In contrast, amplifying the signal through the release of a diffusible inhibitory complex can support reliable checkpoint function. Our results suggest that the design of the spindle checkpoint network is limited by physical constraints imposed by realistic diffusion constants and the relevant spatial and temporal dimensions where computation is performed.modeling ͉ Saccharomyces cerevisiae ͉ cell cycle

Synuclein γ Compromises Spindle Assembly Checkpoint and Renders Resistance to Antimicrotubule Drugs

“…Because SNCG expression overrides the mitotic checkpoint control and confers the cellular resistance to antimicrotubule drug-caused apoptosis, this suggests that the normal mitotic checkpoint function that is required for cells to be arrested at the mitotic phase and the sequent apoptosis by docetaxel is generally impaired in SNCG-expressing cells. Several key proteins for SAC function have been identified, which include BubR1, Mad2, centromere-associated protein-E (CENP-E), Cdc20, and others (39). BubR1 kinase is a key regulator of the SAC.…”

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

“…So far, mathematical models have helped to elucidate the kinetochore structure and with that the mitotic checkpoint mechanism (Doncic et al, 2005;Görlich et al, 2014;Ibrahim et al, 2007;2008b;Ibrahim and Henze, 2014;Kreyssig et al, 2012;Lohel et al, 2009;Sear and Howard, 2006;Simonetta et al, 2009;Tschernyschkow et al, 2013). However, none of these models consider the APC regulatory pathways.…”

“…So far, mathematical models have helped to enlighten crucial modules of the SAC control mechanism, mainly the ''Mad2 template''. Doncic et al (2005) and Sear and Howard (2006) examined simple spatial models of potential checkpoint mechanisms with focus on budding yeast or metazoan, respectively. They found that a diffusible signal can generally account for checkpoint operation.…”

Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase

“…Recently, mathematical modeling of the spindle assembly checkpoint, both in open and closed mitosis, has provided some mechanistic understanding of how the checkpoint could operate (34,35). Doncic et al (34) considered various simplified models of how a single unattached kinetochore could generate a diffusive signal that could prevent the onset of anaphase in yeast.…”

“…This simplified approach is based on the observations that kinetochore-microtubule attachment is a stochastic process (42,43). This in turn has been interpreted as leading to a compound Poisson process governing the state transitions (34) and is the methodology we adopt here. Consider now a simplified state transition process in which only 2 states can occur: the amphitelic state and the unattached state.…”