p53 dynamics in single cells are temperature-sensitive
p53 dynamics in single cells are temperature-sensitive
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DOI：
10.1038/s41598-020-58267-1
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发表时间：
2020-01-30
影响因子：
4.6
通讯作者：
Loewer, Alexander
中科院分区：
文献类型：
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作者：
Jentsch, Marcel;Snyder, Petra;Loewer, Alexander
尽管细胞和物理状态不同，细胞需要保持基因组的完整性。p53是基因组的守护者，通过触发细胞周期停滞、凋亡或衰老，在细胞对DNA损伤的反应中起着至关重要的作用。p53突变或其调控网络的改变是肿瘤发生的主要驱动力。由于多项研究表明，在人类癌症的放疗或化疗期间，热疗具有有益的效果，我们的目的是了解基因毒性应激后p53动力学如何通过生理相关范围内的温度变化进行调节。为此，我们结合使用时间分辨活细胞显微镜和计算分析技术来表征数千个单个细胞中的p53反应。我们的研究结果表明，p53动力学电离辐射是温度依赖性的。在33摄氏度至39摄氏度的范围内，脉动p53动力学在其频率中被调制。高于40摄氏度，这相当于在临床环境中的轻度高热，我们观察到一个可逆的相变，持续过度积累的p53破坏其典型的响应DNA双链断裂。此外，我们提供的证据表明，在没有遗传毒性应激的情况下，单独的轻度高温足以诱导p53反应。这些见解强调了p53介导的DNA损伤反应如何受到细胞物理状态改变的影响，以及如何通过适当的组合疗法来提高癌症治疗的效率。
Cells need to preserve genome integrity despite varying cellular and physical states. p53, the guardian of the genome, plays a crucial role in the cellular response to DNA damage by triggering cell cycle arrest, apoptosis or senescence. Mutations in p53 or alterations in its regulatory network are major driving forces in tumorigenesis. As multiple studies indicate beneficial effects for hyperthermic treatments during radiation- or chemotherapy of human cancers, we aimed to understand how p53 dynamics after genotoxic stress are modulated by changes in temperature across a physiological relevant range. To this end, we employed a combination of time-resolved live-cell microscopy and computational analysis techniques to characterise the p53 response in thousands of individual cells. Our results demonstrate that p53 dynamics upon ionizing radiation are temperature dependent. In the range of 33 degrees C to 39 degrees C, pulsatile p53 dynamics are modulated in their frequency. Above 40 degrees C, which corresponds to mild hyperthermia in a clinical setting, we observed a reversible phase transition towards sustained hyperaccumulation of p53 disrupting its canonical response to DNA double strand breaks. Moreover, we provide evidence that mild hyperthermia alone is sufficient to induce a p53 response in the absence of genotoxic stress. These insights highlight how the p53-mediated DNA damage response is affected by alterations in the physical state of a cell and how this can be exploited by appropriate timing of combination therapies to increase the efficiency of cancer treatments.