The tumor suppressor protein p53 is situated in the midst of a complex network that is activated in response to cellular stress. An unresolved question is how p53 activates its myriad target genes in response to the severity of the stress signal and consequently coordinates the functional outcome in a timely manner. We have previously shown that DNA torsional flexibility distinguishes among p53 response elements (REs). Here we calculated the flexibility of over 200 p53 REs. By connecting functional pathways of p53-dependent genes to the calculated flexibility of their REs, we show that genes belonging to pathways activated rapidly upon stress (e.g., cell-cycle arrest, energy metabolism and innate immunity) contain REs that are significantly more flexible relative to REs of genes involved in pathways that need to be more strictly regulated or are activated later in the response to stress (e.g., intrinsic apoptosis and p53 negative regulation). The global structural properties of several p53 REs belonging to the different pathways were experimentally validated. Additionally, reporter gene expression driven by flexible p53 REs occurred at lower p53 levels and with faster rates than expression from rigid REs. Moreover, analysis of published endogenous mRNA levels of p53 target genes as a function of the flexibility of their REs support our hypothesis. Overall, we demonstrate that DNA flexibility of p53 REs contributes significantly to the timely expression of p53 target genes and thereby plays an important role in cell-faith decisions in the p53 circuity.

中文翻译：

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p53 DNA 结合位点的动力学有助于 p53 驱动基因表达的功能选择性

肿瘤抑制蛋白 p53 位于一个复杂网络的中间，该网络响应细胞压力而被激活。一个未解决的问题是 p53 如何激活其无数靶基因以响应压力信号的严重性，从而及时协调功能结果。我们之前已经表明 DNA 扭转柔度在 p53 反应元件 (REs) 之间存在区别。在这里，我们计算了超过 200 个 p53 RE 的灵活性。通过将 p53 依赖基因的功能通路与其 RE 的计算灵活性联系起来，我们表明属于通路的基因在压力下迅速激活（例如，细胞周期停滞，能量代谢和先天免疫）包含的 REs 相对于涉及需要更严格调节或在应激反应后期被激活的途径（例如内在细胞凋亡和 p53 负调节）中涉及的基因的 REs 显着更加灵活。属于不同途径的几种 p53 RE 的全局结构特性已通过实验验证。此外，由柔性 p53 RE 驱动的报告基因表达发生在较低的 p53 水平，并且比刚性 RE 的表达速度更快。此外，对已发表的 p53 靶基因的内源性 mRNA 水平作为其 RE 灵活性的函数的分析支持我们的假设。全面的，