p53 dynamics in response to DNA damage vary across cell lines and are shaped by efficiency of DNA repair and activity of the kinase ATM.

Cellular systems show a wide range of signaling dynamics. Many of these dynamics are highly stereotyped, such as oscillations at a fixed frequency. However, most studies looking at the role of signaling dynamics focus on one or a few cell lines, leaving the diversity of dynamics across tissues or cell lines a largely unexplored question. We focused on the dynamics of the tumor suppressor protein p53, which regulates cell cycle arrest and apoptosis in response to DNA damage. We established live-cell reporters for 12 cancer cell lines expressing wild-type p53 and quantified p53 dynamics in response to double-strand break-inducing DNA damage. In many of the tested cell lines, we found that p53 abundance oscillated in response to ionizing radiation or the DNA-damaging chemotherapeutic neocarzinostatin and that the periodicity of the oscillations was fixed. In other cell lines, p53 abundance dynamically changed in different ways, such as a single broad pulse or a continuous induction. By combining single-cell assays of p53 signaling dynamics, small-molecule screening in live cells, and mathematical modeling, we identified molecules that perturbed p53 dynamics and determined that cell-specific variation in the efficiency of DNA repair and the activity of the kinase ATM (ataxia-telangiectasia mutated) controlled the signaling landscape of p53 dynamics. Because the dynamics of wild-type p53 varied substantially between cell lines, our study highlights the limitation of using one line as a model system and emphasizes the importance of studying the dynamics of other signaling pathways across different cell lines and genetic backgrounds.