Transcription Factor Ztf-17 Regulates Oxidative Stress Responses in Caenorhabditis Elegans

Energy production is a biological process required for life by all living organisms. However, this process exerts a major effect on aging as metabolism of nutritive energy at the mitochondria inevitably generates reactive oxygen species (ROS). ROS are by-products of cellular metabolism and have important physiological roles in cell signaling and homeostasis but can also harbor harmful effects. Because ROS readily react with other macromolecules, if ROS formation exceeds a physiological level and antioxidants are unable to balance out the damaging effects of ROS, a dangerous condition known as oxidative stress occurs. This accumulation of cellular damage severely compromises cell health and contributes to the onset of age-associated diseases. Many organisms have complex antioxidant systems to protect themselves and in Caenorhabditis elegans, SKN-1/Nrf2 and DAF-16/FOXO, promote the expression of stress resistance genes that aid in detoxifying ROS. Our lab has previously shown that transcription factors can influence the expression of phase II detoxifying genes, through SKN-1 activation, while phase I genes can be activated through DAF-16 which confer stress resistance. An RNAi screen against transcription factor ZTF-17 revealed thatSKN-1 target, gst-4p::gfpexpression, was enhanced. This suggested that ZTF-17 possessed repressor like functions during oxidative stress responses. I confirmed that ZTF-17 significantly reduced the activity of SKN-1 and DAF-16 on the skn-1cp and sod-3p target promoters indicating that ZTF-17 may interact directly and/or indirectly with the DNA to modulate transcription through repression. Analysis through various experiments using ztf-17(tm963) deletion mutants showed that genes related to oxidative stress, lifespan and longevity were enhanced to promote short-term oxidative stress resistance, but interestingly, mutants also had compromised heat shock survival. The stress regulatory network is extremely complex, and although detoxification processes exist, the molecular players involved in maintaining proper function under oxidative stress remains unclear. Thus, my investigation of ZTF-17s function along with characterizing its role as a potential negative regulator will help elucidate the mechanism to achieve stress resistance and the implications this has on lifespan and longevity.