After completing her PhD at the University of Utah, Liz Fedak continued to work with the Schiffman and Adler Labs as a postdoctoral researcher. Her interest in complex systems lead her to mechanistic cancer modeling, starting with tumor-immune system interactions and most recently centering around DNA damage repair and cell fate pathways. In the future, she hopes to extend dynamical systems theory to help modelers in her field balance detail and parsimony, a problem she once summarized on Twitter as ”you can model the Death Star as a sphere, but you’re going to miss the exhaust port.”
p53 is one of the most widely studied proteins in molecular biology because of its central role in tumorigenesis. In a healthy, replicating cell, p53 makes cell fate decisions based on signals it receives from repair pathways. These signals do not correspond exactly to the total amount of damage in the cell; rather, comparably lethal amounts of damage can induce dissimilar signals if their associated repair pathways operate at different speeds. For example, γ radiation induces DNA lesions that p53-activating kinases bind to within minutes, while the DNA lesions created by UV radiation only communicate with p53-activating kinases during repair.
Using a mechanistic model, we argue that this difference in response speed causes distinct dynamical profiles of p53 to arise. For strong, transient signals, autoregulatory mechanisms activate to prevent premature apoptosis, causing oscillations. For low, persistent signals, the cell stabilizes inactive p53, compensating for lower activating-enzyme levels by increasing the substrate concentration. Other models have focused on the mechanistic cause of p53 oscillations; this model provides a hypothesis as to why they exist.
Our mechanistic model resolves several claims about p53 and its upstream pathways. Here we focus on the surprising hypotheses that arise from reconciling p53’s paradoxical behavior.