Regulation of the Oxidative Stress Response by ZTF-17 in Caenorhabditis elegans

Reactive oxygen species (ROS) are common by-products of normal cellular metabolism and have important physiological roles in cell signaling and homeostasis. However, when there is an excess production of ROS, a dangerous condition known as oxidative stress (OS) occurs where by the body is overwhelmed and unable to detoxify these free radicals. ROS readily react with other macromolecules causing damage to DNA, lipids and proteins, severely compromising cell health and contributes to the onset of age-associated diseases. Many organisms have devised antioxidant systems to protect themselves and in Caenorhabditis elegans, two important transcription factors, SKN-1/Nrf2 and DAF-16/FOXO promote the expression of stress resistance genes. Phase II detoxifying genes such as gst-4 is expressed through SKN-1, while sod-3 is under DAF-16 control, and both confer stress resistance when activated. When an RNAi against transcription factor ZTF-17 was used, enhanced gst-4p::gfp expression was observed suggesting that ZTF-17 possessed repressor like functions. ZTF-17 is uncharacterized but its mammalian homolog, ZFP42/REX1, is a pluripotency factor that represses transcription of the Xist gene during X-chromosome inactivation. We observed that ztf-17(tm963) deletion mutants had increased gst-4p::gfp and sod-3p::gfp expression and confirmed by qRT-PCR that mRNA levels of both genes were significantly enhanced when compared to wild type. Although the detoxification process exists, the mechanism by which the levels of free radicals are regulated and the molecular players involved in maintaining proper function under OS remains unclear. Our lab aims to investigate ZTF-17’s function along with characterizing its role as a potential negative regulator of SKN-1 and DAF-16 target genes implicated in the OS response, lifespan and longevity.