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 (SKN-1 in Caenorhabditis elegans). Nrf2/SKN-1 activation promotes the induction of the Phase II detoxification system that serves to limit oxidative stress. We have extended a previous C. elegans genetic approach to explore the mechanisms by which a Phase II enzyme is induced by endogenous and exogenous oxidants. The xrep ( xenobiotics response pathway) mutants were isolated as defective in their ability to regulate properly the induction of a glutathione S-transferase (GST) reporter. The
xrep-1 gene was previously identified as
wdr-23, which encodes a C. elegans homolog of the mammalian B-propeller repeat-containing protein WDR-23. Here, we identify and confirm the mutations in
xrep-2,
xrep-3, and
xrep-4 The
xrep-2 gene is
alh-6, an ortholog of a human gene mutated in familial hyperprolinemia. The
xrep-3 mutation is a gain-of-function allele of
skn-1 The
xrep-4 gene is F46F11.6, which encodes a F-box-containing protein. We demonstrate that
xrep-4 alters the stability of WDR-23 (
xrep-1), a key regulator of SKN-1 (
xrep-3). Epistatic relationships among the xrep 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.