Significance: The p53 tumor suppressor has been dubbed the "guardian of genome" because of its various roles in the response to DNA damage such as DNA damage repair, cell cycle arrest, senescence, and apoptosis, all of which are in place to prevent mutations from being passed on down the lineage. Recent Advances: Reactive oxygen species (ROS), for instance hydrogen peroxide derived from mitochondrial respiration, have long been regarded mainly as a major source of cellular damage to DNA and other macromolecules. Critical Issues: More recently, ROS have been shown to also play important physiological roles as second messengers in so-called redox signaling. It is, therefore, not clear whether the observed activation of p53 by ROS is mediated through the DNA damage response, redox signaling, or both. In this review, we will discuss the similarities and differences between p53 activation in response to DNA damage and redox signaling in terms of upstream signaling and downstream transcriptional program activation. Future Directions: Understanding whether and how DNA damage and redox signaling-dependent p53 activation can be dissected could be useful to develop anti-cancer therapeutic p53-reactivation strategies that do not depend on the induction of DNA damage and the resulting additional mutational load.
Keywords: DNA damage; cancer therapeutics; cysteine oxidation; p53; redox sigaling.