title: Stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage.
abstract: A massive integrative mathematical model of DNA double-strand break (DSB) generation, DSB repair system, p53 signaling network, and apoptosis induction pathway was constructed to explore the dominant factors of unknown criteria of cell fate decision. In the proposed model, intranuclear reactions were modeled as stochastic processes and cytoplasmic reactions as deterministic processes, and both reaction sets were simulated simultaneously. The simulated results at the single-cell level showed that the model generated several sustained oscillations (pulses) of p53, Mdm2, ATM, and Wip1, and cell-to-cell variability in the number of p53 pulses depended on IR intensity. In cell populations, the model generated damped p53 oscillations, and IR intensity affected the amplitude of the first p53 oscillation. Cells were then subjected to the same IR dose exhibiting apoptosis induction variability. These simulated results are in quantitative agreement with major biological findings observed in human breast cancer epithelial MCF7, NIH3T3, and fibrosarcoma cells, demonstrating that the proposed model was concededly biologically appropriate. Statistical analysis of the simulated results shows that the generation of multiple p53 pulses is a prerequisite for apoptosis induction. Furthermore, cells exhibited considerable individual variability in p53 dynamics, which correlated with intrinsic apoptosis induction. The simulated results based on the proposed model demonstrated that the stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage. Applying stochastic simulation to an exploration of intranuclear biochemical reaction processes is indispensable in enhancing the understanding of the dynamic characteristics of biological multi-layered systems of higher organisms.
authors.affiliation: Graduate school of Systems Life Sciences, Kyushu University, Fukuoka, Japan; Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Iwamoto
authors.affiliation: Department of Systems Life Sciences, Kyushu University, Fukuoka, Japan; Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; Synthetic Systems Biology Research Center, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Kyushu University Bio-Architecture Center, Kyushu University, Fukuoka, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Eguchi
authors.affiliation: Department of Systems Life Sciences, Kyushu University, Fukuoka, Japan; Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; Synthetic Systems Biology Research Center, Kyushu University, Fukuoka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okamoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001669:Biochemical Phenomena; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism* / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D011829:Radiation Dosage; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53