Plausible, robust biological oscillations through allelic buffering.

Cell systems Pub Date : 2024-11-20 Epub Date: 2024-11-05 DOI:10.1016/j.cels.2024.10.002
Feng-Shu Hsieh, Duy P M Nguyen, Mathias S Heltberg, Chia-Chou Wu, Yi-Chen Lee, Mogens H Jensen, Sheng-Hong Chen
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Abstract

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.

通过等位基因缓冲实现可信、稳健的生物振荡。
生物振荡器可以通过对其振荡动态的专门控制,实现与时间和剂量相关的功能。然而,生物振荡器反复激活嘈杂的生化过程,如何实现稳健振荡仍不清楚。在这里,我们描述了 DNA 损伤后单细胞中 p53 及其负反馈调节因子 Mdm2 的长期振荡。p53 的振荡是有规律的,而来自单个 MDM2 等位基因的 Mdm2 则对 p53 脉冲的 9%~9% 随机无反应。利用MDM2活性的等位基因特异性成像,我们发现MDM2等位基因会相互缓冲,以维持p53脉冲的振幅。消除 MDM2 等位基因的缓冲作用会削弱 p53 脉冲幅度的稳健性,从而提高 p21 水平并导致细胞周期停滞。硅模拟支持等位基因缓冲增强了生物振荡器的稳健性,并拓宽了其合理的生物化学空间。我们的研究结果表明了等位基因缓冲如何确保了 p53 振荡的稳健性,突出了等位基因缓冲对于进化过程中出现稳健生物振荡器的潜在重要性。补充信息中包含了本文透明的同行评审过程记录。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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