Spatiotemporal Redox Regulation of Cell-Cycle Progression: Dynamic Functions of Cellular Redox Regulatory Proteins

Abstract

Highlights What are the main findings? Redox regulation is dynamically coordinated with cell-cycle progression through phase-specific changes in H2O2 generation, sensing, buffering, and resolution. MnSOD, peroxiredoxins, Nrf2/HO-1/NQO1, glutathione, glutaredoxins, GPXs, and the thioredoxin system perform complementary functions that link redox homeostasis with proliferation, DNA replication, checkpoint control, and mitosis. What are the implications of the main findings? Cell-cycle progression depends on maintaining a defined redox signaling window that permits physiological H2O2 signaling while limiting oxidative damage. Disruption of this coordinated redox network may contribute to genomic instability, aberrant proliferation, and cancer-cell survival, highlighting redox vulnerabilities as potential therapeutic targets. Abstract Aerobic life revolves around the enigmatic role of oxygen, which sustains the life cycle by supporting energy production while simultaneously threatening its existence through the generation of reactive oxygen species (ROS). Intriguingly, ROS are not merely by-products of energy generation; cells actively invest in their production through dedicated pro-oxidant systems. A long-standing perception in the scientific community has been that cellular antioxidant systems primarily evolved as terminators of ROS to protect against oxidative damage. It appears paradoxical, however, that the complex, multilayered antioxidant defense built by cells may actually relay, propagate, and buffer ROS in a spatiotemporal manner rather than simply scavenge them. Perpetuation of life essentially depends upon the cell cycle, one of the most orderly and tightly regulated cellular events. While several elegant reviews have highlighted that cell-cycle regulatory proteins are subject to redox modifications and that changes in cellular redox state influence cell-cycle fate, the converse relationship has received relatively less attention. Proteins regulating cellular antioxidant defense themselves undergo cell-cycle phase-specific changes in their abundance, activity, and localization. There therefore appears to be a coordinated and integrated redox network operating during cell-cycle progression. Here, we examine this relationship from a protein-centric perspective, focusing on MnSOD/H2O2, peroxiredoxins, Nrf2, HO-1, NQO1, glutathione, glutathione peroxidases, glutaredoxins, and the thioredoxin/thioredoxin reductase system. Although these systems have often been studied independently, their functions overlap and change as cells move through G1, S, G2, and mitosis. We propose that cell-cycle progression should be viewed as a dynamically regulated redox process in which spatiotemporally organized oxidative signals provide an additional regulatory layer operating alongside the classical cell-cycle machinery.