Venkatachalapathy Harish, Dallon Samuel, Yang Zhilin, Azarin Samira M, Sarkar Casim A, Batchelor Eric
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN, 55455, USA.
Mol Syst Biol. 2025 Apr;21(4):390-412. doi: 10.1038/s44320-025-00091-8. Epub 2025 Mar 3.
Oscillatory p53 expression occurs in individual cells responding to DNA breaks. While the majority of cells exhibit the same qualitative response, quantitative features of the oscillations (e.g., amplitude or period) can be highly variable between cells, generating heterogeneity in downstream cell fate responses. Since heterogeneity can be detrimental to therapies based on DNA damage, methods to induce synchronization of p53 oscillations across cells in a population have the potential to generate more predictable responses to DNA-damaging treatments. Using mathematical modeling and time-lapse microscopy, we demonstrated that p53 oscillations can be synchronized through the phenomenon of phase resetting. Surprisingly, p53 oscillations were synchronized over a wider range of damage-induction frequencies than predicted computationally. Recapitulating the range of synchronizing frequencies required, non-intuitively, a less robust oscillator. We showed that p53 phase resetting altered the expression of downstream targets responsible for cell fate depending on target mRNA stability. This study demonstrates that p53 oscillations can be phase reset and highlights the potential of driving p53 dynamics to reduce cellular variability and synchronize cell fate responses to DNA damage.
振荡性p53表达出现在对DNA断裂作出反应的单个细胞中。虽然大多数细胞表现出相同的定性反应，但振荡的定量特征（如振幅或周期）在细胞之间可能有很大差异，从而在下游细胞命运反应中产生异质性。由于异质性可能对基于DNA损伤的治疗有害，因此诱导群体中细胞间p53振荡同步的方法有可能对DNA损伤治疗产生更可预测的反应。通过数学建模和延时显微镜，我们证明p53振荡可以通过相位重置现象实现同步。令人惊讶的是，p53振荡在比计算预测更宽的损伤诱导频率范围内实现了同步。重现所需的同步频率范围，非直观地，需要一个不太稳健的振荡器。我们表明，p53相位重置根据靶mRNA稳定性改变了负责细胞命运的下游靶标的表达。这项研究表明p53振荡可以进行相位重置，并突出了驱动p53动态变化以减少细胞变异性并使细胞对DNA损伤的命运反应同步的潜力。
