Topic Overview:

Cells in our body from normal tissues and tumors show a range of sensitivities to DNA damage from ionizing radiation or chemotherapy. Ubiquitously expressed, the transcription factor p53 regulates the radiosensitivity of many tissues. As both sensitive and resistant tissues and tumors express p53, cell-type specific regulatory control of p53 temporal dynamics and DNA binding are critical to determining the response to DNA damage. Using a combination of genomic, evolutionary, single-cell, and tissue-level techniques to study p53’s role in diverse cellular contexts, Stewart-Ornstein and colleagues show that cellular chromatin state and signaling dynamics of p53 contribute to cell fate in radio- and chemo-therapy and that pharmacological modulation of p53 behavior alters cellular, tissue, and tumor radiosensitivity. These results highlight the role of feedback control in p53 signaling and show how this control is tuned to generate diverse signaling dynamics and outcomes in different tissues and species. Stewart-Ornstein will discuss the implications of this research toward understanding the physiological and homeostatic role of p53 and DNA damage signaling and commonalities with other stress responses.