A Genetic Analysis of the Detoxification Response.

Oxidative damage contributes to human diseases of aging including diabetes, cancer, and cardiovascular disorders. Reactive oxygen species resulting from xenobiotic and endogenous metabolites are sensed by a poorly understood process, triggering a cascade of regulatory factors and leading to the activation of the transcription factor Nrf2 (Nuclear factor-erythroid-related factor 2, SKN-1 in ). Nrf2/SKN-1 activation promotes the induction of the phase II detoxification system that serves to limit oxidative stress. We have extended a previous genetic approach to explore the mechanisms by which a phase II enzyme is induced by endogenous and exogenous oxidants. The () mutants were isolated as defective in their ability to properly regulate the induction of a glutathione -transferase (GST) reporter. The gene was previously identified as , which encodes a homolog of the mammalian β-propeller repeat-containing protein WDR-23 Here, we identify and confirm the mutations in , , and The gene is , an ortholog of a human gene mutated in familial hyperprolinemia. The mutation is a gain-of-function allele of The gene is , which encodes a F-box-containing protein. We demonstrate that alters the stability of WDR-23 (), a key regulator of SKN-1 (). Epistatic relationships among the mutants and their interacting partners allow us to propose an ordered genetic pathway by which endogenous and exogenous stressors induce the phase II detoxification response.