A quantitative model of the effect of unreplicated DNA on cell cycle progression in frog egg extracts

Abstract

A critical goal in cell biology is to develop a systems-level perspective of eukaryotic cell cycle controls. Among these controls, a complex signaling network (called ‘checkpoints’) arrests progression through the cell cycle when there is a threat to genomic integrity such as unreplicated or damaged DNA. Understanding the regulatory principles of cell cycle checkpoints is important because loss of checkpoint regulation may be a requisite step on the roadway to cancer. Mathematical modeling has proved to be a useful guide to cell cycle regulation by revealing the importance of bistability, hysteresis and time lags in governing cell cycle transitions and checkpoint mechanisms. In this report, we propose a mathematical model of the frog egg cell cycle including effects of unreplicated DNA on progression into mitosis. By a stepwise approach utilizing parameter estimation tools, we build a model that is grounded in fundamental behaviors of the cell cycle engine (hysteresis and time lags), includes new elements in the signaling network (Myt1 and Chk1 kinases), and fits a large and diverse body of data from the experimental literature. The model provides a validated framework upon which to build additional aspects of the cell cycle checkpoint signaling network, including those control signals in the mammalian cell cycle that are commonly mutated in cancer.