The p53 tumor suppressor protein maintains the genome fidelity and integrity by modulating several cellular activities. It regulates these events by interacting with a heterogeneous set of response elements (REs) of regulatory genes in the background of chromatin configuration. At the p53-RE interface, both the base readout and torsional-flexibility of DNA account for high-affinity binding. However, DNA structure is an entanglement of a multitude of physicochemical features, both local and global structure should be considered for dealing with DNA-protein interactions. The goal of current research work is to conceptualize and abstract basic principles of p53-RE binding affinity as a function of structural alterations in DNA such as bending, twisting, and stretching flexibility and shape. For this purpose, we have exploited high throughput in-vitro relative affinity information of responsive elements and genome binding events of p53 from HT-Selex and ChIP-Seq experiments respectively. Our results confirm the role of torsional flexibility in p53 binding, and further, we reveal that DNA axial bending, stretching stiffness, propeller twist, and wedge angles are intimately linked to p53 binding affinity when compared to homeodomain, bZIP, and bHLH proteins. Besides, a similar DNA structural environment is observed in the distal sequences encompassing the actual binding sites of p53 cistrome genes. Additionally, we revealed that p53 cistrome target genes have unique promoter architecture, and the DNA flexibility of genomic sequences around REs in cancer and normal cell types display major differences. Altogether, our work provides a keynote on DNA structural features of REs that shape up the in-vitro and in-vivo high-affinity binding of the p53 transcription factor.

p53 肿瘤抑制蛋白通过调节多种细胞活动来维持基因组的保真度和完整性。它通过在染色质构型的背景下与一组异质的调节基因的反应元件 (RE) 相互作用来调节这些事件。在 p53-RE 界面上，DNA 的碱基读数和扭转灵活性均是高亲和力结合的原因。然而，DNA 结构是多种物理化学特征的纠缠，在处理 DNA-蛋白质相互作用时应考虑局部和全局结构。当前研究工作的目标是将 p53-RE 结合亲和力的基本原理概念化和抽象化，作为 DNA 结构改变的函数，例如弯曲、扭曲和拉伸的灵活性和形状。为此，我们利用了高吞吐量体外分别来自 HT-Selex 和 ChIP-Seq 实验的 p53 响应元件和基因组结合事件的相对亲和力信息。我们的结果证实了扭转灵活性在 p53 结合中的作用，此外，我们揭示了与同源域、bZIP 和 bHLH 蛋白相比，DNA 轴向弯曲、拉伸刚度、螺旋桨扭曲和楔角与 p53 结合亲和力密切相关。此外，在包含 p53 cistrome 基因实际结合位点的远端序列中观察到类似的 DNA 结构环境。此外，我们发现 p53 cistrome 靶基因具有独特的启动子结构，并且癌症和正常细胞类型中 RE 周围基因组序列的 DNA 灵活性显示出重大差异。总而言之，我们的工作提供了关于 REs 的 DNA 结构特征的主题演讲，这些特征塑造了p53 转录因子的体外和体内高亲和力结合。