Prediction of the Behavior of Mammalian Cells after Exposure to Ionizing Radiation Based on the New Mathematical Model of ATM-Mdm2-p53 Regulatory Pathway

Abstract

Eukaryotic cells are exposed continuously to the genotoxic stresses caused by various sources, such as ionizing radiation (IR) that generates DNA double-strand breaks (DSBs). In order to maintain genomic integrity, the DNA damage response is activated. DSBs are detected by ATM protein kinase that stabilizes and activates p53 tumor suppressor, which target genes are involved in cell cycle arrest, DNA repair and apoptosis. We propose a preliminary mathematical model that explains p53 regulation based on ATM-dependent detector system. We linked the existing p53-Mdm2 pathway model with checkpoint kinase 2 that inhibits p53 degradation, and MRN complex that activates ATM upon DSBs induction. Moreover, recent works shown that the critical component of ATM-dependent signaling pathway is played by phosphatase Wip1 that regulates dephosphorylation events. Additionally, in the presented model we included Wip1 transcriptionally dependent on p53. The preliminary results of simulation analysis show that ATM pathway is an effective system for DSBs detection with strong amplification signal for Wip1 and p53 and quick response. Furthermore, we observed strong dependence of the cellular response to the DNA damage on Wip1, what leads to the conclusion that it plays a role as a gatekeeper in the ATM-Mdm2-p53 regulatory loop.