A role for DNA-mediated charge transport in regulating p53: Oxidation of the DNA-bound protein from a distance
| Autor: | Jacqueline K. Barton, Katherine E. Augustyn, Edward J. Merino |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
DNA Repair Photochemistry Protein Conformation Base pair DNA repair Anthraquinones Cell Cycle Proteins Electrophoretic Mobility Shift Assay Oxidative phosphorylation Redox Electron Transport chemistry.chemical_compound Oxidants Photochemical Consensus Sequence Organometallic Compounds Promoter Regions Genetic Multidisciplinary Cell Cycle Nuclear Proteins Proto-Oncogene Proteins c-mdm2 Promoter DNA Electron transport chain Intercalating Agents Oxidative Stress Biochemistry chemistry Physical Sciences Biophysics Cystine Tumor Suppressor Protein p53 Biological regulation Oxidation-Reduction Caltech Library Services Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:18907-18912 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Charge transport (CT) through the DNA base pairs provides a means to promote redox reactions at a remote site and potentially to effect signaling between molecules bound to DNA. Here we describe the oxidation of a cell-cycle regulatory protein, p53, from a distance through DNA-mediated CT. A consensus p53 binding site as well as three DNA promoters regulated by p53 were synthesized containing a tethered DNA photooxidant, anthraquinone. Photoinduced oxidation of the protein occurs from a distance; introduction of an intervening CA mismatch, which inhibits DNA-mediated CT, prevents oxidation of p53. DNA-mediated oxidation is shown to promote dissociation of p53 from only some promoters, and this sequence-selectivity in oxidative dissociation correlates with the biological regulation of p53. Under severe oxidative stress, effected here through oxidation at long range, p53 dissociates from a promoter that activates DNA repair as well as the promoter for the negative regulator of p53, Mdm2, but not from a promoter activating cell-cycle arrest. Mass spectrometry results are consistent with disulfide bond formation in p53 upon DNA-mediated oxidation. Furthermore, DNA-bound p53 oxidation is shown in vivo by up-regulation of p53 and subsequent irradiation in the presence of a rhodium photooxidant to give a new p53 adduct that can be reversed with thiol treatment. This DNA-mediated oxidation of p53 parallels that seen by treating cells with hydrogen peroxide. These results indicate a unique mechanism using DNA-mediated CT chemistry by which p53 activity on different promoters may be controlled globally under conditions of oxidative stress. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|