pH-driven conformational switch between non-canonical DNA structures in a C-rich domain of EGFR promoter
| Autor: | Riccardo Rigo, Claudia Sissi, Camilla Cristofari, Maria Laura Greco, Michele Ghezzo |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Guanine Stereochemistry Phenanthroline lcsh:Medicine Article Receptor tyrosine kinase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Humans Binding site Promoter Regions Genetic lcsh:Science Binding Sites Multidisciplinary biology Oncogene Chemistry lcsh:R DNA Hydrogen-Ion Concentration ErbB Receptors G-Quadruplexes 030104 developmental biology Intramolecular force Domain (ring theory) biology.protein Nucleic Acid Conformation lcsh:Q Tyrosine kinase 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-37968-8 |
| Popis: | EGFR is an oncogene that encodes for a trans-membrane tyrosine kinase receptor. Its mis-regulation is associated to several human cancers that, consistently, can be treated by selective tyrosine kinase inhibitors. The proximal promoter of EGFR contains a G-rich domain located at 272 bases upstream the transcription start site. We previously proved it folds into two main interchanging G-quadruplex structures, one of parallel and one of hybrid topology. Here we present the first evidences supporting the ability of the complementary C-rich strand (EGFR-272_C) to assume an intramolecular i-Motif (iM) structure that, according to the experimental conditions (pH, presence of co-solvent and salts), can coexist with a different arrangement we referred to as a hairpin. The herein identified iM efficiently competes with the canonical pairing of the two complementary strands, indicating it as a potential novel target for anticancer therapies. A preliminary screening for potential binders identified some phenanthroline derivatives as able to target EGFR-272_C at multiple binding sites when it is folded into an iM. |
| Databáze: | OpenAIRE |
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