Oxidation of p53 via DNA-mediated charge transport

Abstract

Transcription factor p53 plays a crit. role in the cellular response to stress stimuli. Previous studies have shown that p53 dissocs. from its response element upon oxidative DNA- mediated charge transport (CT) . This oxidative dissocn. of p53 via DNA CT depends on the integrity of the π- stacked DNA bases and guanine locations within the response element. Greater p53 dissocn. is obsd. from sequences contg. 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 det. residues within p53 that enable oxidative dissocn. by DNA CT, select p53 mutations were explored. Electrophoretic mobility shift assays using oligonucleotides contg. tethered anthraquinone for long- range photooxidn. were used to det. the influence of each mutation on oxidative dissocn. Differential thiol labeling and multiple reaction monitoring mass spectrometry were used to investigate cysteine oxidn. within p53 from a distance via DNA CT. It is proposed that disulfide formation involving C275 is crit. for inducing oxidative dissocn. of p53 from DNA.

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© 2015 American Chemical Society.

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