DREAM/KChIP3 (Downstream Regulatory Element Antagonist Modulator) is a multifunctional Ca2+-binding protein that acts in the nucleus as a Ca2+-dependent transcriptional repressor. Binding to DNA and repressor activity of DREAM is regulated by Ca2+, specific post-translational modifications as well as by protein–protein interactions with several nucleoproteins. Here, using the yeast two-hybrid assay, we characterized the interaction of DREAM with peroxiredoxin 3 (Prdx3), an antioxidant enzyme that uses the thioredoxin system as electron donor. Importantly, the DREAM/Prdx3 interaction is Ca2+ dependent and is blocked by DTT. Coexpression of Prdx3 enhances DREAM binding to DRE sites and its repressor activity in vivo. Two cysteine residues in the N-terminal domain of DREAM are responsible for the redox modulation of its activity. Double Cys to Ser substitution results in a mutant DREAM with stronger repressor activity. Finally, we show that transient DREAM knockdown sensitizes PC12 cells to H2O2-induced oxidative stress, suggesting a protective role for DREAM against oxidative damage. Antioxid. Redox Signal. 14, 1237–1243.
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