TIGP (BIO)—How p53 Keeps the Beat: Allelic Buffering Sustains Robust Oscillations

Abstract

Biological oscillators are ubiquitous in nature, coordinating cellular functions in space and time through recurrent activation of their feedback loops. However, these feedback loops involve multi-step biochemical reactions that inherently generate and amplify stochastic noise. How biological oscillators sustain long-term oscillatory dynamics despite this noise remains unclear. Here, using p53—a key regulator of cell fate—as a paradigm, we identify a novel mechanism, allelic buffering, that enhances oscillator robustness. While p53 oscillates regularly in response to DNA double-stranded breaks, Mdm2 expressed from a single allele exhibits stochastic unresponsiveness in ~9% of p53 pulses. Allele-specific imaging reveals that MDM2 alleles compensate for each other, preserving p53 pulse amplitude. Disrupting this buffering mechanism impairs p53 amplitude robustness, leading to increased p21 levels and prolonged cell-cycle arrest. Computational modeling supports that allelic buffering enhances the resilience of biological oscillators and broadens the biochemical parameter space that supports oscillatory behavior. Our findings demonstrate how allelic buffering stabilizes p53 oscillations and suggest that similar mechanisms may have contributed to the evolution of robust biological oscillators.

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