Unifying the mechanism of mitotic exit control in a spatiotemporal logical model.

Rowan S. M. Howell,Cinzia Klemm,Attila Csikász-Nagy,Peter H. Thorpe,Jonathon Pines

doi:10.1371/journal.pbio.3000917

Abstract

The transition from mitosis into the first gap phase of the cell cycle in budding yeast is controlled by the Mitotic Exit Network (MEN). The network interprets spatiotemporal cues about the progression of mitosis and ensures that release of Cdc14 phosphatase occurs only after completion of key mitotic events. The MEN has been studied intensively; however, a unified understanding of how localisation and protein activity function together as a system is lacking. In this paper, we present a compartmental, logical model of the MEN that is capable of representing spatial aspects of regulation in parallel to control of enzymatic activity. We show that our model is capable of correctly predicting the phenotype of the majority of mutants we tested, including mutants that cause proteins to mislocalise. We use a continuous time implementation of the model to demonstrate that Cdc14 Early Anaphase Release (FEAR) ensures robust timing of anaphase, and we verify our findings in living cells. Furthermore, we show that our model can represent measured cell-cell variation in Spindle Position Checkpoint (SPoC) mutants. This work suggests a general approach to incorporate spatial effects into logical models. We anticipate that the model itself will be an important resource to experimental researchers, providing a rigorous platform to test hypotheses about regulation of mitotic exit.

Highlights

The ordering of mitotic events is tightly controlled in eukaryotes in order to ensure accurate chromosome segregation and prevent aneuploidy, a hallmark of cancer [1]
This meant we introduced a node called “Cdc5OE” which had the same outputs as Cdc5 in the Prior Knowledge Network (PKN), this node was treated as all the others in the training process
The “Cdc5OE” node was removed during integration with the Mitotic Exit Network (MEN) model, but its effect was recovered by the addition of overexpression nodes for each protein in the model

Summary

Introduction

The ordering of mitotic events is tightly controlled in eukaryotes in order to ensure accurate chromosome segregation and prevent aneuploidy, a hallmark of cancer [1]. The Mitotic Exit Network (MEN) is a signalling network in Saccharomyces cerevisiae that interprets spatial and temporal signals in late mitosis, ensuring mitotic exit and cytokinesis occur only after proper segregation of the genetic material (reviewed in [2,3,4,5,6,7]). Since the network was first described by Jaspersen and colleagues [8], over 100 papers have been published on the topic. This volume of research has driven the MEN to become one of the best understood signalling pathways; it poses a challenge to synthesise this knowledge. We propose a compartmental, logical model of the MEN that aims to represent a unified view of the network and make predictions about its behaviour.

Objectives

Methods

Results

Conclusion