FIG. 6.

ROS feedback to the clock. Cytoplasmic ROS act as a posttranslational modifier and signaling molecule, directing the cell to increase antioxidant defense. H₂O₂ in the cytoplasm will interact directly with CLOCK and oxidize cysteine195. This oxidation event promotes dimerization between CLOCK and BMAL1 and their subsequent nuclear translocation. Cytoplasmic H₂O₂ will also stimulate NRF2 nuclear translocation and activity. BMAL1 targets NRF2, which will promote further antioxidant defense. NRF2 targets Cry2 and Nr1d1, which will act as a negative feedback mechanism to inhibit BMAL1 transcriptional activity and reduce the antioxidant response.