New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins

• Published in: Structure (London) Vol. 26; no. 9; pp. 1237 - 1250.e6
• Main Authors: Golovenko, Dmitrij, Bräuning, Bastian, Vyas, Pratik, Haran, Tali E., Rozenberg, Haim, Shakked, Zippora
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 04.09.2018
• Subjects: binding affinity and stability; DNA structure; p53 transcription factor; protein-DNA recognition; DNA structure; p53 transcription factor; binding affinity and stability; protein-DNA recognition
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2018.06.006

The tumor suppressor p53 acts as a transcription factor recognizing diverse DNA response elements (REs). Previous structural studies of p53-DNA complexes revealed non-canonical Hoogsteen geometry of A/T base pairs at conserved CATG motifs leading to changes in DNA shape and its interface with p53. To study the effects of DNA shape on binding characteristics, we designed REs with modified base pairs “locked” into either Hoogsteen or Watson-Crick form. Here we present crystal structures of these complexes and their thermodynamic and kinetic parameters, demonstrating that complexes with Hoogsteen base pairs are stabilized relative to those with all-Watson-Crick base pairs. CATG motifs are abundant in p53REs such as GADD45 and p53R2 related to cell-cycle arrest and DNA repair. The high-resolution structures of these complexes validate their propensity to adopt the unique Hoogsteen-induced structure, thus providing insights into the functional role of DNA shape and broadening the mechanisms that contribute to DNA recognition by proteins. [Display omitted] •Modified bases “lock” DNA base pairs at Hoogsteen (HG) or Watson-Crick geometry•HG base pairs enhance binding affinity and stability of p53-DNA complexes•DNA targets with CATG motifs are predisposed to HG-induced shape upon binding to p53•Interactions between arginine residues and the DNA backbone support HG base pairs To study the effect of DNA shape on its interaction with the tumor-suppressor p53, Golovenko et al. used modified bases constraining specific base pairs to either Hoogsteen or Watson-Crick geometry. The high-resolution structures and binding data demonstrate that the unique Hoogsteen-induced DNA shape leads to enhanced stabilization of p53-DNA complexes.