SEM-4 is a Novel Protein in the BRAP-2/SKN-1/ROS Detoxification Pathway

Oxidative stress causes damage to cells by creating reactive oxygen species (ROS). The overproduction of ROS is detrimental, having been linked to the onset of premature ageing and age-related diseases. Our lab has previously found that a partial deletion of brap-2 (BRCA-1 associated protein 2) significantly increased the expression of gst-4, a phase II detoxification enzyme in C.elegans. An RNAi screen for 940 transcription factors on a brap-2;gst-4::gfp strain resulted in more than 20 candidates that are proposed to alter expression of gst-4 in BRAP- 2/SKN-1/ROS detoxification pathway, and one of those genes, sem-4, was chosen for the further studies. A significant reduction in gst-4 mRNA levels was observed in sem-4;brap-2 double mutants and sem-4 mutants. We also found that higher levels of ROS were generated in sem-4 mutants in comparison to N2 worms, indicating that SEM-4 is required to prevent overproduction of ROS in vivo. Furthermore, the lifespan of skn-1 overexpressing worms was dependent on presence of sem-4. Next, survival of worms exposed to constant oxidative stress was decreased in sem-4 mutants. Lastly, we determined that SEM-4 is a transcriptional regulator of skn-1c. Together, these results indicate a newly identified role of SEM-4 in regulating expression of phase II detoxification enzymes and preventing the harmful effects caused by overproduction of ROS