Redox regulation of the Cdc25 phosphatases

The Cdc25 phosphatases are essential for cell-cycle control in eukaryotes under normal conditions and in response to DNA damage via checkpoint controls. Recent evidence indicates direct control of the Cdc25s, and therefore the cell cycle, in response to changes in cellular redox status. These redox changes may originate intracellularly from mitochondrial leakage or in response to specific external triggers leading to production of reactive oxygen species (ROS). This review shows that the known chemistry and biology of the Cdc25s favor a direct role for these phosphatases in temporarily blocking cell-cycle progression until favorable reducing conditions are restored. First, the Cdc25s contain a highly reactive cysteine at the active site that can react directly with ROS, leading to enzyme inactivation. Second, the ROS-inactivated form of Cdc25 is expected to prevent cell-cycle progression based on precedent from cellular responses to DNA damage. Third, ROS-mediated oxidation of the Cdc25s leads to an intramolecular disulfide that is readily reversible by the cellular reductant thioredoxin. Finally, in vivo data supporting a direct role for the Cdc25s in redox regulation are considered.