Genetic resonance in the p53 signaling network

Resonance allows systems to amplify their response to periodic stimuli and is well established in physics but not yet described in gene regulatory networks. Here, we asked whether resonance exists in the dynamics of p53, a tumor suppressor that oscillates after DNA damage to activate growth-inhibitory pathways. We developed a mathematical framework predicting that p53 exhibits damped oscillations after a single stimulus and frequency-dependent amplitudes under periodic stimulation, both hallmarks of resonance. Using live single-cell imaging, we confirmed these predictions: a single drug pulse that stabilizes p53 produced damped oscillations, while periodic pulses triggered frequency-dependent responses with maximal amplitudes at the natural p53 oscillation frequency as well as minor peaks. Finally, theoretical analysis suggested that resonance may enhance transcriptional responses and selectively activate downstream targets. Together, our results identify resonance as a regulatory principle in gene networks, potentially linking oscillations of transcription factors with selective gene activation through signal amplification.