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Transcriptional regulators of oxidative stress responses in the nematode Caenorhabditis elegans Goh, Ying Shyen

Abstract

Reactive oxygen species are chemically reactive molecules that are crucial for many cellular functions, but their buildup can cause toxic damage, otherwise known as oxidative stress. Oxidative stress is thought to cause or exacerbate many diseases. To defend themselves against oxidative stress, cells mount sophisticated defenses to remove ROS and repair damage caused by ROS. In particular, sequence-specific DNA binding transcription factors induce the expression of cytoprotective enzymes upon stress. In the model organism Caenorhabditis elegans, the transcription factor SKN-1 is considered a “master regulator” that is required to activate many cytoprotective and antioxidant genes, and is critical for resistance to oxidative stress. However, little is known about whether and how SKN-1 interacts with transcriptional coregulators, essential factors that help specify transcriptional responses. Moreover, although evidence exists for SKN-1 independent oxidative stress responses, the responsible transcription factors are unknown. In this thesis, I identified a subunit of the Mediator transcriptional coregulator complex, MDT-15, as a coregulator for skn-1-dependent oxidative stress responses. This role is independent of a previously identified role for MDT-15 in lipid metabolism. Additionally, I found that mdt-15 is also required for skn-1-independent oxidative stress responses. Using a candidate reverse genetic screen, I identified an MDT-15-interacting transcription factor, the nuclear hormone receptor NHR-49, as a regulator of a SKN-1-independent oxidative stress response. Interestingly, some NHR-49-dependent stress response genes were also upregulated in fasting and in long-lived germline-less mutants, indicating a shared response in all three conditions. In summary, this thesis provides the first description of MDT-15 as a coregulator of SKN-1 and identifies a new role for NHR-49 in the oxidative stress response. SKN-1, NHR-49, and MDT-15 are all conserved in humans, and the human orthologs of SKN-1 and NHR-49 also interact with the Mediator complex. Thus, my work offers therapeutic implications for diseases in which oxidative stress plays a role, such as cancer, metabolic diseases, and other age-related diseases.

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