Transcription factor p53 controls many cellular processes in response to cellular stress. As a redox-active protein, p53 binds DNA in its reduced state and dissociates upon oxidation. Transcription factor p53 can be directly oxidized via DNA-mediated charge transport (DNA-CT). The ability of certain consensus sites to be responsive to DNA-CT induced oxidation of p53 correlates to the oxidation potential of the consensus sequence nucleobases. Greater p53 oxidative dissociation is observed from consensus sequences containing purine sequences with low oxidation potential; a guanine triplet is far more favorable to conduct DNA-CT to p53 than an adenine triplet. This characteristic property was studied in vitro by EMSA and guanine oxidation PAGE assays among multiple unnatural and human p53 consensus sequence oligonucleotides tethered with an anthraquinone photooxidant. EMSAs of mutant p53 have indicated that cysteine 275 is a key residue for successful p53 oxidative dissociation by DNA-CT. To determine which of the 10 cysteine residues in pseudo-wild type and mutant p53 form a terminal disulfide pair within the oxidized protein, differential thiol labeling characterized by mass spectrometry is being utilized.

DNA-mediated oxidation of transcription factor p53: Dependence upon DNA sequence and cysteine residues

246th National Meeting (2013)

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