Mathematical modelling of p53 basal dynamics and DNA damage response

A gene that plays a crucial role in the regulation of cell life and death is the tumour suppressor gene p53, which encodes protein p53. The p53 tumour suppressor protein is regarded as the “guardian of the genome”, which is a transcription factor, that activates genes that result in DNA repair, cell cycle arrest, senescence (permanent cell cycle arrest) or apoptosis (programmed cell death) in response to various stress signals that could induce genetic instability. Recent individual cell studies have indicated that p53 activation is highly regulated in response to stress conditions and in unstressed normal proliferating cells. The aim of this research is to investigate the design principles behind the precise regulation of p53 activation. We develop a mathematical model using delay differential equations that incorporate the most recently found molecular interactions and genes regulated by p53, such as p53 activation of MdmX and Wip1, in the core regulation of p53 in normal proliferating cells and cells under DNA damage stress. We model the p53 core regulatory feedback mechanisms that control p53 levels. Experiments have shown that after DNA damage – DNA double-strand breaks (DSBs) – p53 levels show a series of repeated pulses. Whereas in non-stressed conditions with intrinsic DNA damage, one or two spontaneous pulses (basal dynamics) were observed. Figure 1 shows a schematic diagram of the model hypothesis. We found that the core regulatory network consists of ATM, Mdm2, MdmX, Wip1 and p53, and it reproduced simulations consistent with the experimental findings. Our results show that the p53 spontaneous pulses are due to intrinsic DNA double strand breaks in normal proliferating cells. Local parameter sensitivity analysis identified Wip1 as the major component that controlled the period of p53 oscillations. Despite its simplicity, our model is a mechanistic model that presents a dynamic hypothesis of molecular interactions that control p53 activation