Parkinson, C.; March-Steinman, W.; Jose, E.; Shanks, L.; Paek, A. L.

Hydrogen Peroxide (H2O2) stress activates transcription factors (TFs) in a dose-dependent manner, with distinct TFs activated in response to low versus high H2O2. Here, we show that high H2O2 imposes a translational constraint that prevents accumulation of TFs requiring de novo protein synthesis. Under low H2O2 conditions, TFs including p53, NRF2, and ATF4, accumulate and drive stress-responsive gene expression. In contrast, high H2O2 induces coordinated inhibition of translation initiation and elongation through activation of the integrated stress response (ISR), suppression of mTORC1 signaling, and activation of eEF2K, thereby blocking accumulation of these TFs. Inhibition of translation and repression of p53, NRF2, and ATF4 coincides with nuclear shuttling of pre-existing TFs, including FOXO1, NFAT1, and NF-{kappa}B. We propose that shuttling TFs provide a backup mechanism to respond to severe oxidative stress while translation is inhibited. Together, these findings identify translational control as a central switch governing transcription factor response to H2O2 stress.