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Pulsed stimuli entrain p53 to synchronize single cells and modulate cell-fate determination
Biorxiv : the Preprint Server for Biology
|November 14, 2023
Summary
The p53 protein
Area of Science:
- Cellular dynamics and signaling pathways
- Biophysics of biological oscillators
- DNA damage response mechanisms
Background:
- Entrainment synchronizes cellular responses, but its role in intrinsic single-cell oscillations is unknown.
- The p53 protein oscillates following DNA double-strand breaks (DSBs), crucial for cell fate decisions.
- Understanding p53 entrainability is key to exploring therapeutic modulation of cellular responses.
Approach:
- Mathematical modeling to predict p53 oscillation dynamics.
- Time-lapse fluorescence microscopy for real-time cellular observation.
- Single-cell tracking to analyze individual p53 oscillation responses to periodic DSB stimuli.
Key Points:
- p53 oscillations can be entrained by periodic DNA damage stimuli, even without known population synchrony benefits.
- Experimental entrainment occurred over a broader frequency range than computational models predicted.
- A less robust oscillator and wider energy landscape valley were required to match experimental entrainment ranges.
- Entrainment alters downstream target gene expression dynamics, influencing cell fate outcomes.
- Altered expression dynamics depend on target mRNA stability.
Conclusions:
- Demonstrates entrainment in a biological oscillator lacking apparent evolutionary advantage for synchrony.
- Highlights potential for externally entraining p53 dynamics to reduce cellular variability.
- Suggests therapeutic applications in synchronizing cell-fate responses for improved outcomes.
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