The phase II detoxification system is an important cellular defence against the toxic effects of free radicals and xenobiotics which cause oxidative tissue damage that has been implicated in many diseases and in ageing. Thus, in response to stress, the expression of many phase II detoxification enzyme genes is co-ordinately induced. The antioxidant glutathione is utilized as an important component of many phase II detoxification reactions.g-glutamine cysteine synthetase, encoded by
gcs-1, catalyses the rate-limiting step in glutathione biosynthesis. Thus
gcs-1 is amongst the phase II detoxification genes that are transcriptionally activated in response to stress. Conserved bZIP transcription factors, including Nrf-2 in mammals and SKN-1 in C. elegans, are required for regulation of phase II detoxification genes, including
gcs-1. Several signaling pathways including the PMK-1/p38 MAPK signaling pathway, act to regulate levels of active SKN-1 which is important for both stress resistance and ageing [1, 2]. However, in the absence of the conserved 2-Cys Peroxiredoxin PRDX-2, expression of phase II detoxification genes such as
gcs-1 is also activated by alternative SKN-1-independent mechanisms [3]. Moreover, activation by these SKN-1-independent mechanism/s is apparently sufficient to increase resistance to arsenite stress. To determine the mechanism/s by which PRDX-2 inhibits phase II detoxification gene expression, we are undertaking RNAi screens to identify genes required for expression of a stress-inducible Pgcs-1::GFP reporter in
prdx-2 mutant worms. Phosphatases play key roles in the regulation of signal transduction and are intrinsically sensitive to oxidative stress. Hence, we have begun by conducting a screen of RNAi targeting C. elegans phosphatase-encoding genes. Here we will present the data obtained in this screen. It is expected that characterisation of genes identified by these screens will uncover new mechanisms for regulating phase II detoxification gene expression and provide insight into the important contributions made by PRDX-2 and phase II detoxification systems to stress resistance and longevity [2, 3].