Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle

Kazunari Kaizu,Hisao Moriya,Hiroaki Kitano,Orna Cohen-Fix

doi:10.1371/journal.pgen.1000919

Abstract

Cells can maintain their functions despite fluctuations in intracellular parameters, such as protein activities and gene expression levels. This commonly observed biological property of cells is called robustness. On the other hand, these parameters have different limitations, each reflecting the property of the subsystem containing the parameter. The budding yeast cell cycle is quite fragile upon overexpression of CDC14, but is robust upon overexpression of ESP1. The gene products of both CDC14 and ESP1 are regulated by 1∶1 binding with their inhibitors (Net1 and Pds1), and a mathematical model predicts the extreme fragility of the cell cycle upon overexpression of CDC14 and ESP1 caused by dosage imbalance between these genes. However, it has not been experimentally shown that dosage imbalance causes fragility of the cell cycle. In this study, we measured the quantitative genetic interactions of these genes by performing combinatorial “genetic tug-of-war” experiments. We first showed experimental evidence that dosage imbalance between CDC14 and NET1 causes fragility. We also showed that fragility arising from dosage imbalance between ESP1 and PDS1 is masked by CDH1 and CLB2. The masking function of CLB2 was stabilization of Pds1 by its phosphorylation. We finally modified Chen's model according to our findings. We thus propose that dosage imbalance causes fragility in biological systems.

Highlights

Intracellular biochemical parameters, such as gene expression levels and protein activities, are highly optimized in order to maximize the performance of biological systems [1,2,3,4]
The yeast cell cycle can be maintained despite significant overexpression of most genes within the system, the cell cycle halts upon just two-fold overexpression of M phase phosphatase CDC14
We experimentally showed that this fragility is caused by dosage imbalance between CDC14 and NET1

Summary

Introduction

Intracellular biochemical parameters, such as gene expression levels and protein activities, are highly optimized in order to maximize the performance of biological systems [1,2,3,4]. These parameters operate within certain limitations to maintain the function of the system against perturbations such as environmental changes, mutations, and noise in biochemical reactions. This robustness against fluctuations in parameters is considered a common design principle of biological systems [5,6,7]. Cell cycle regulation has been integrated into a mathematical model called Chen’s model [9] This model implements interactions of about 25 genes involved in the budding yeast cell cycle to reproduce over 100 mutant phenotypes, and has become a standard for measuring the robustness of the budding yeast cell cycle [10,11,12]

Methods

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Discussion

Conclusion