Cellular responding DNA damage: An improved modeling of P53 gene regulatory networks under ion radiation (IR)

Abstract

As a vital anticancer gene, P53 controls the cell cycle arrest and cell apoptosis by regulating a series of genes and their complicated signal pathways. To simulate the self-defensive mechanisms of the cellular responding DNA damage under continuous ion radiation (IR), an improved model of the P53 gene regulatory networks is proposed at single cell level. The model can be used to simulate the kinetics of the double-strand breaks (DSBs) generating and their repair, ataxia telangiectasia mutated (ATM) and ARF activation, as well as the regulations of the P53–MDM2 feedback loop. Also, the model can predict the plausible outcomes of cellular responding DNA damage under different IR dose domains.

Introduction

Under genome stresses such as DNA damage, hypoxia, and aberrant oncogene signals, cells can trigger their internal defensive mechanisms in fighting against these perturbations from outsides [1], [2], [3]. One critical response is the activation of the tumor suppressor P53, which can control the transcription and translation of series downstream genes. By regulating the complicated signal pathways, P53 induce or repress the expression level of the vital genes within the cell, leading to cell cycle arrest and cell apoptosis in response to genome stresses induced by abnormal signals from outsides [5]. Induction of apoptosis indirectly triggered by P53 is pivotal for eliminating abnormal cells with genome damage by irradiation or chemotherapeutic drugs [4], [5]. Whereas, abnormalities in the P53 tumor suppressor have been identified in over 60% of human cancers and the status of P53 within tumor cells has been proposed to be one of the determinant response to anticancer therapies [3]. Furthermore, controlled radiotherapy studies show the existence of a strong biologic basis for considering P53 status as a radiation predictor [6], [7], therefore, P53 status in tumor cell can be considered as a predictor for long-term biochemical control during and after radiotherapy [7], [8].

The combined approaches of systems analysis, control theory, and computer science can stimulate new approaches to simulate the investigation of the complicated mechanisms of cellular responding genome stresses [9], [10]. These methods provide a good link between the diverging areas of biomedicine and mathematics [11]. Using differential equations and graphic approaches to study various dynamical and kinetic processes of biological systems can provide useful insights, as indicated by many previous studies on a series of important biological topics, such as enzyme-catalyzed reactions, etc. [11], [12], [13].

Recently, several models have been proposed to explain the damped oscillations of P53 in cell populations [14], [15], [16], [17], [18]. However, under continuous effect of acute IR, the complicated mechanisms of cellular response in fighting against DNA damage need to be further addressed at single cell level. To simulate the kinetics of cellular self-defense in response to different IR dose, an improved model of P53 gene regulatory networks is proposed based on the previous models [14], [15], [16], [17], [18] and latest biomedical studies [19], [20]. In our model, the dynamics of double-strand breaks (DSBs) generating and their repairing, ATM and ARF activation, as well as the regulatory kinetics of P53–MDM2 feedback loop are implemented by using a set of differential equations. Meanwhile, the plausible outcomes of cellular responding DNA damage are presented versus continuous radiation time within different IR dose domains.