Transcription factor p53 plays a critical role in the cellular response to stress stimuli. Previous studies have shown that p53 dissociates from its response element upon oxidative DNA-mediated charge transport (CT). This oxidative dissociation of p53 via DNA CT depends on the integrity of the π-stacked DNA bases and guanine locations within the response element. Greater p53 dissociation is observed from sequences containing low redox potential purine regions, particularly guanine doublets and triplets. Oxidative DNA damage is inhibited in the presence of p53, but only at sites in direct contact with p53. To determine residues within p53 that enable oxidative dissociation by DNA CT, select p53 mutations were explored. Electrophoretic mobility shift assays using oligonucleotides containing tethered anthraquinone for long-range photooxidation were used to determine the influence of each mutation on oxidative dissociation. Differential thiol labeling and multiple reaction monitoring mass spectrometry were used to investigate cysteine oxidation within p53 from a distance via DNA CT. It is proposed that disulfide formation involving C275 is critical for inducing oxidative dissociation of p53 from DNA.

Oxidation of p53 via DNA-mediated charge transport

249th National Meeting (2015)

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