Plausible, robust biological oscillations through allelic buffering

Biological oscillators can specify time- and dose-dependent functions via dedicated control of their oscillatory dynamics. However, how biological oscillators, which recurrently activate noisy biochemical processes, achieve robust oscillations remains unclear. Here, we characterize the long-term oscillations of p53 and its negative feedback regulator Mdm2 in single cells after DNA damage. Whereas p53 oscillates regularly, Mdm2 from a single MDM2 allele exhibits random unresponsiveness to ∼9% of p53 pulses. Using allelic-specific imaging of MDM2 activity, we show that MDM2 alleles buffer each other to maintain p53 pulse amplitude. Removal of MDM2 allelic buffering cripples the robustness of p53 amplitude, thereby elevating p21 levels and cell-cycle arrest. In silico simulations support that allelic buffering enhances the robustness of biological oscillators and broadens their plausible biochemical space. Our findings show how allelic buffering ensures robust p53 oscillations, highlighting the potential importance of allelic buffering for the emergence of robust biological oscillators during evolution. A record of this paper's transparent peer review process is included in the supplemental information.