Dynamics of the p53 response to ionizing and ultraviolet radiation

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Abstract
The tumor suppressor protein p53 compiles information about cellular stressors to make decisions on whether the cell should survive or undergo apoptosis. However, the p53 response depends on the source of damage, displaying a ‘digital’ oscillatory response after ionizing radiation (IR) damage and a proportional non-oscillatory response following UV damage. We propose a mathematical model that qualitatively replicates this observed behavior. The difference in p53 dynamics in the model results from two mechanisms: IR damage is fully detected minutes after exposure while UV damage is detected over several hours; and the p53-controlled transcriptional response is dominated by inactive p53 following UV damage. In particular, we hypothesize that an unidentified positive feedback loop controlled by inactive p53 is required to maintain the qualitative high p53 response to UV damage. This work proposes an explanation for two distinct responses of p53 to DNA damage and how each response can lead to cell cycle arrest or apoptosis. Author summary: We propose a mathematical model hypothesizing how the tumor suppressor protein p53 produces two contrasting dynamical responses in response to different types of DNA damage. In particular, we predict the existence of a positive feedback loop controlled by the inactive form of p53, which allows the cell to respond to slowly detected damage. The existence of differing dynamic responses by p53 has implications for our understanding of tumor development and possibly p53-related therapeutic strategies.

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