Background: Occurrence of p53 mutations in more than half of human tumors indicates the importance of p53 gene in cancer prevention. Nevertheless, oxidation of cysteine-SH groups in p53 protein can inactivate the protein under oxidative conditions. The importance of p53 as a tumor suppressor and insufficient studies about redox regulation of p53 gene lead us to study redox regulation of p53 protein. Methods: In this study, yeast (Saccharomyces cerevisiae) was used as an in vivo model. All potential thiol-dependent antioxidant genes in yeast were identified based on specific characters in their structure, via REDOXCysSearch bioinformatics tool. To study human p53 gene activity in yeast cells, p53 gene and p53 RE Lac-Z reporter that is inducible by p53, were transformed into yeast. Antioxidant gene mutants were analyzed for LacZ reporter gene activity. Results: We identified several yeast mutants (Δsac1, Δhnt3 and Δmap1) with lower p53 activity with respect to wild-type yeast. Conclusion: Due to conserved mechanisms of cell cycle regulation and oxidative stress tolerance between yeast and mammals, we believe that results from yeast studies may help us to understand the redox regulation of p53 in human cells. Thus, a new perspective may appear in the redox regulation of p53 gene.