A quantitative model of the effect of unreplicated DNA on cell cycle progression in frog egg extracts.
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.
Zwolak
Jason
J
Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, 24061, USA. jzwolak@vt.edu
Adjerid
Nassiba
N
Bagci
Elife Z
EZ
Tyson
John J
JJ
Sible
Jill C
JC
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D000071877:Checkpoint Kinase 1; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology; D008938:Mitosis / Q000235:genetics; D008957:Models, Genetic; D010063:Ovum / Q000166:cytology; D011494:Protein Kinases / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology; D029867:Xenopus Proteins / Q000502:physiology; D014982:Xenopus laevis / Q000235:genetics
D004268:DNA-Binding Proteins; C489725:Myt1 protein, Xenopus; D014157:Transcription Factors; D029867:Xenopus Proteins; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605875:Chek1 protein, Xenopus