Research ArticleCell Biology

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

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Science Signaling  25 Apr 2017:
Vol. 10, Issue 476, eaah6671
DOI: 10.1126/scisignal.aah6671

Variations in p53 dynamics

A cell’s response to changes in its extracellular or intracellular environment (the path between signal and output) involves complex molecular networks. These networks are temporally dynamic, requiring investigators to consider multiple time points when analyzing pathway activity. Using single-cell imaging, Stewart-Ornstein and Lahav showed not only that DNA damage dynamically induced the tumor suppressor protein p53, which regulates cell cycle arrest and apoptosis, but also that those dynamics varied between cell lines, even of the same tissue type. The findings provide insight into the p53-mediated DNA damage response in multiple cell types. Because many other signaling pathways likely demonstrate this high degree of variability, the study also reveals that making generalized assumptions about cell signaling behavior based on a single cell line, or even one line for each tissue, is prone to error.


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.

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