Mechanisms of High Zinc Tolerance, Sensing, and Homeostasis in C. elegans

What are the mechanisms used by animals to cope with stressful environments that inflict damage or restrict essential processes such as growth, development, and reproduction? Furthermore, how do animals cope with the variety of stresses encountered throughout life, including fluxes in heat, oxidation, and metal availability? We propose 2 possible models explaining how animals respond to the diversity of environmental stress: (1) diverse environmental stresses converge on a single type of important molecular damage. For example, heat, oxidation, and excess metals may all cause toxicity as a result of similar damage, such as protein unfolding. In this model, changing the activity of a single gene might confer broad-spectrum stress resistance by enhancing tolerance to the major form of cellular damage. (2) Animals possess specific mechanisms to cope with very specific stresses such as high zinc. For example, the individual stress high cellular zinc is dealt with in a zinc specific manner via efflux or chelation. Here I describe the discovery and characterization of 2 new genes natc-1 and nhr-33, which modulate the response of Caenorhabditis elegans to environmental stress in very different manners. NATC-1 is an N-terminal acetyltransferase that modulates resistance to a broad spectrum of stressors as a downstream effector of the insulin/IGF-1 signaling pathway. NHR-33 is a nuclear receptor that responds directly and specifically to high zinc to promote the transcription of genes that reduce high zinc toxicity. Therefore, this thesis work describes the discovery and characterization of 2 distinct molecular mechanisms used by the animal model C. elegans to cope with stress, allowing animals to efficiently grow, develop, and reproduce in variable and complex environments