title: Mathematical modelling of p53 basal dynamics and DNA damage response.
abstract: The p53 tumour suppressor protein is a transcription factor that activates genes that result in cell cycle arrest, DNA damage repair, senescence or apoptosis. Recent individual cell studies have indicated that p53 activation is highly regulated in response to stressed conditions and non-stressed (normal proliferating) conditions in cells. The aim of this research is to investigate the design principles behind the precise regulation of p53 activation, under normal and stressed conditions. We extended the Sun et al. (2011) mathematical model of delay differential equations by incorporating the most recently found molecular interactions and hypotheses. In particular, we found that the core regulatory network consists of ATM, Mdm2, MdmX, Wip1 and p53. Our model of the p53 core regulatory feedback mechanisms can reproduce a series of repeated pulses in stressed conditions with appropriate induction of cell cycle arrest, and one or two spontaneous pulses (basal dynamics) in non-stressed conditions and these are consistent with the recent experimental findings. Our results show that the p53 spontaneous pulses are due to intrinsic DNA double strand breaks in normal proliferating cells, and p53 auto-regulation (positive feedback loop) allows threshold activation of p53 in generating these pulses. It also shows that the p53 dynamics are excitable; bifurcation analysis revealed a spectrum of p53 behaviour under stressed and non-stressed (normal) conditions on the basis of stress signal activation rate, and characterised p53 dynamics as Type II excitability. Additionally, the model makes testable predictions on pharmacological intervention to reactivate p53. Importantly, we reveal novel findings on the mechanism of threshold activation of p53 pulsatile and oscillatory dynamics that are important for its physiological function as the guardian of the genome.
authors.affiliation: Integrated Systems Modelling Group and Centre for Advanced Computational Solutions (C-fACS), Lincoln University, Christchurch, New Zealand.
authors.forename: Ket Hing
authors.initials: KH
authors.lastname: Chong
authors.affiliation: Integrated Systems Modelling Group and Centre for Advanced Computational Solutions (C-fACS), Lincoln University, Christchurch, New Zealand; Department of Informatics and Enabling Technologies, Lincoln University, Christchurch, New Zealand. Electronic address: sandhya.samarasinghe@lincoln.ac.nz.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Samarasinghe
authors.affiliation: Integrated Systems Modelling Group and Centre for Advanced Computational Solutions (C-fACS), Lincoln University, Christchurch, New Zealand; Department of Molecular Biosciences, Lincoln University, Christchurch, New Zealand.
authors.forename: Don
authors.initials: D
authors.lastname: Kulasiri
mesh_terms: D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: DNA damage response; Mathematical models; Spontaneous pulses; p53 basal dynamics; p53 oscillations; p53 pulsatile dynamics