Symphony of the DNA flexibility and sequence environment orchestrates p53 binding to its responsive elements.

Abstract

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.