Dynamics of the p53 response to ionizing and ultraviolet radiation

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 summaryWe 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. PLOS2/15 1 Although the functional purpose of p53 within a cell has been widely studied, its 2 dynamics have yet to be fully characterized. The p53 tumor suppressor protein, 3 mutated in 50% of all cancers, is responsible for activating cell cycle arrest or apoptosis 4 programs following cellular stress [1][2][3][4]. To guide these decisions, p53 must integrate 5 information about stress from multiple sources-including DNA damage, hypoxia, 6 transcriptional stress, and telomere erosion-that each affect its total level and 7 activation dynamics differently. It is unknown how p53 controls cell cycle arrest and 8 apoptosis through these dynamical changes. 9Particularly interesting early work demonstrated that oscillations in total p53 level 10 with a consistent period and amplitude were observed in MCF7 cells exposed to 11 γ-radiation, inspiring a generation of dynamical p53 models [5]. When the same types 12 of cells were exposed to UV light, however, no such oscillations were observed; total p53 13 instead increased proportional to the amount of induced damage [6]. Both phenomena 14 have also been observed in non-cancerous cells [7, 8]. Researchers have characterized the 15 first response as digital, and the second as proportional [6]. In this work, we use 16 mathematical models to explore what causes this difference in behavior, and further 17 hypothesize why this change in dynamics is necessary for the p53-mediated apoptotic 18 pathway to function after exposure to each type of damage. 19 ...