Diverse p53/DNA binding modes expand the repertoire of p53 response elements
| Autor: | Zippora Shakked, Itai Beno, Zhiqun Xi, Naama Kessler, Tali E. Haran, Varda Rotter, Dmitrij Golovenko, Pratik Vyas, Yan Stein |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Genetics Multidisciplinary Base pair Stereochemistry DNA Biological Sciences Biology Response Elements 03 medical and health sciences chemistry.chemical_compound genomic DNA 030104 developmental biology chemistry Humans Protein–DNA interaction Tumor Suppressor Protein p53 Binding site Transcription factor Gene Protein Binding P53 binding |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:10624-10629 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The tumor suppressor protein p53 acts as a transcription factor, binding sequence-specifically to defined DNA sites, thereby activating the expression of genes leading to diverse cellular outcomes. Canonical p53 response elements (REs) are made of two decameric half-sites separated by a variable number of base pairs (spacers). Fifty percent of all validated p53 REs contain spacers between 1 and 18 bp; however, their functional significance is unclear at present. Here, we show that p53 forms two different tetrameric complexes with consensus or natural REs, both with long spacers: a fully specific complex where two p53 dimers bind to two specific half-sites, and a hemispecific complex where one dimer binds to a specific half-site and the second binds to an adjacent spacer sequence. The two types of complexes have comparable binding affinity and specificity, as judged from binding competition against bulk genomic DNA. Structural analysis of the p53 REs in solution shows that these sites are not bent in both their free and p53-bound states when the two half-sites are either abutting or separated by spacers. Cell-based assay supports the physiological relevance of our findings. We propose that p53 REs with long spacers comprise separate specific half-sites that can lead to several different tetrameric complexes. This finding expands the universe of p53 binding sites and demonstrates that even isolated p53 half-sites can form tetrameric complexes. Moreover, it explains the manner in which p53 binds to clusters of more than one canonical binding site, common in many natural REs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|