Zinc is a metal element that is essential for life, but is toxic when present in excess. Cells therefore rely on mechanisms to maintain a relatively constant intracellular level of zinc despite fluctuations in the extracellular medium. To ensure that zinc levels are maintained at an optimal level for cell metabolism, the expression of genes necessary for zinc transport or zinc storage is often dependent upon cellular zinc levels. Although such changes in gene expression are central to zinc homeostasis, the identity of the factors that sense intracellular zinc levels and mediate these changes is largely unknown. The long-term goal of our research is to understand how eukaryotic cells sense and regulate intracellular zinc levels. To identify proteins that sense zinc, we have taken advantage of the versatile genetics of Schizosaccharomyces pombe. Using this model system we have isolated a novel factor that is required for zinc-dependent regulation of gene expression. This factor, designated Loz1, contains a double C2H2-type zinc finger domain that is essential for zinc-dependent regulation of gene expression. This proposal describes a combined molecular, genetic and biochemical approach to determine how Loz1 is regulated by zinc. Specifically, we will address whether Loz1 directly senses zinc levels, and whether this requires the double C2H2-type zinc finger domain.
Zinc deficiency is a significant health issue. For example, zinc deficiency in children leads to an increased risk of diarrhea, pneumonia, and malaria. Low dietary zinc levels also lead to an increased risk of sepsis-related mortality. Abnormal cellular zinc levels have been associated with a range of disorders including esophageal cancers, prostate cancers, pancreatic cancers, and Alzheimer's disease. The studies outlined in this application will provide insight into the types of domains that can be use to sense intracellular zinc levels. This knowledge will aid in the identification of proteins whose activity is modulated by zinc, and will further our knowledge of the connection between zinc and specific diseases. PUBLIC HEALTH RELEVANCE: Imbalances in zinc levels have been observed in a wide variety of disorders, including diabetes, breast cancer, prostate cancer, and esophageal and oral cancers. The goal of our research is to determine the mechanisms by which eukaryotic cells sense and regulate intracellular zinc levels. This information will provide important insight into the role of zinc in health and disease.
