Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

Area of Science:

• Cellular biology
• Molecular oncology
• Systems biology

Background:

• DNA double-strand breaks (DSBs) trigger complex repair pathways.
• Phosphatidylinositol 3-kinase (PI3K)-like kinases, including DNA-PK and ATM, are crucial for DSB repair and p53 activation.
• Previous studies noted amplified p53 signaling under DNA-PK inhibition, but the underlying dynamics were not theoretically modeled.

Purpose of the Study:

• To develop a theoretical model characterizing prolonged p53 pulses under DNA-PK inhibition.
• To investigate the dose-dependent effects of DNA-PK inhibition on p53 dynamics.
• To explore the impact of DNA-PK inhibition on information flow within the p53 signaling pathway.

Main Methods:

• Mathematical modeling of the p53 signaling network.
• Simulations incorporating DNA-PK inhibition.
• Analysis of p53 pulse amplitude, width, and information flow dynamics.

Main Results:

• The model successfully replicated dose-dependent increases in the amplitude and width of the first p53 pulse under DNA-PK inhibition.
• Weakened DNA-PK-mediated ATM inhibition alone was insufficient to reproduce the observed dynamics.
• A significant shift of information flow predominantly to the first p53 pulse was observed.
• The amplified p53 responses demonstrated relative robustness.

Conclusions:

• The developed theoretical model accurately captures amplified p53 responses to DNA-PK inhibition.
• The findings provide insights into how manipulating p53 dynamics influences cell fate decisions following DNA damage.
• The study highlights the critical role of DNA-PK in regulating p53 signaling kinetics.