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

A Framework for Modeling the Cellular Defending Mechanisms Against Genome Stress Under Radiotherapy

“…Under the genome stresses, many efforts have been made to enhance P53-mediated transcription through some models [58,59] [9][10][11][12]. However, the interactions in a real system would make these models [60] extremely complicated.…”

“…Compared with the previous models [9][10][11][12], the current model contains more vital components, such as oncogenes, ARF and mP53, as well as their related regulating pathways. In the DSBs generation and repair module, the acute IR induces DSBs stochastically and forms DSB-protein complexes (DSBCs) at each of the damage sites after interacting with the DNA repair proteins [2,3].…”

“…As shown in Fig.4, P53 and its principal antagonist, MDM2 transactivated by P53, form a P53-MDM2 feedback loop, which is the core part in the integrated networks [9][10][11][12]. ATM* elevates the transcriptional activity of P53 by prompting phosphorylation of P53 and degradation of MDM2 protein [67].…”

“…Shown in Fig.3 is the module scheme of ATM and ARF activation, which includes five components: ATM dimer, inactive ATM monomer, ATM*, ARF, and ARF*. Compared with the previous studies in [9][10][11][12], ARF, oncogenes, and the related signal pathways are involved in this module [2,7. Here, let us assume that DSBCs is the main signal transduction from DSBs to P53-MDM2 feedback loop through ATM activation, and the rate of ATM activation is a function of the amount of DSBCs, ARF* and the self-feedback of ATM*. Furthermore, the total concentration of ATM is a constant, including ATM dimer, ATM monomer and ATM, as treated in {Ma, 2005 #1194].…”

“…Each DSB can be in one of the four states: intact DSB, DSBC, Fr and Fw [9,10,12]. Thus, we have the following differential equations:…”