Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

Abstract

The shape of dose response of ionizing radiation (IR) induced cancer at low dose region, either linear non-threshold or J-shaped, has been a debate for a long time. This dose response relationship can be influenced by built-in capabilities of cells that minimize the fixation of IR-mediated DNA damage as pro-carcinogenic mutations. Key capabilities include sensing of damage, activation of cell cycle checkpoint arrests that provide time needed for repair of the damage as well as apoptosis. Here we describe computational modeling of the signaling pathways that link sensing of DNA damage and checkpoint arrest activation/apoptosis to investigate how these molecular-level interactions influence the dose response relationship for IR induced cancer. The model provides qualitatively accurate descriptions of the IR-mediated activation of cell cycle checkpoints and the apoptotic pathway, and of time-course activities and dose response of relevant regulatory proteins (e.g. p53 and p21). Linking to a two-stage clonal growth cancer model, the model described here successfully captured a monotonically increasing to a J-shaped dose response curve and identified one potential mechanism leading to the J-shape: the cell cycle checkpoint arrest time saturates with the increase of the dose.