Date of Award

5-6-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Dr. John E. Houghton

Second Advisor

Dr. Julia Hilliard

Third Advisor

Dr. Taras Nazarko

Abstract

Cadmium (Cd), a heavy metal found in the earth’s crust, poses a significant health risk as industrialization has resulted in its entry into our food supply. This toxin targets multiple organ systems and is known to be carcinogenic. Many of the deleterious effects caused by Cd have been attributed to its indirect production of ROS, leading to a highly oxidative state within cells. The majority of Cd studies have assessed chronic exposure and use concentrations that humans are unlikely to be exposed to. Using the model organism S. cerevisiae, this study attempts to map out the molecular mechanisms governing short term exposure to low-levels of Cd through a global ‘omics’ approach. Through this it was found that within the first hour of exposure DNA damage, protein misfolding, and stress response pathways were activated while transcription and translation pathways were impaired. Believing this to be a result of oxidative stress, this study found that there was no presence of ROS despite a measurable increase in protein carbonylation. Assessing nitrosative stress, however, showed that exposure to low levels of Cd resulted in a 166% increase in NO. High concentrations of intracellular NO causes deleterious effects similar to that of ROS. Studies have shown that SIRT1, a histone deacetylase, and FOXO1, a forkhead box transcription factor, are mediators of the response to rising NO levels. However, as NO increases, SIRT1 can be inactivated due to S-nitrosylation of its catalytic core. This study determined that the yeast homologues Sir2p and Hcm1p mediate part of the cells response to Cd insult, and that Sir2p-Hcm1p interaction was inhibited, resulting in the prevention of Hcm1p from translocating into the nucleus. This resulted in a downregulation of Hcm1p-dependent transcription. These effects persisted beyond the hour of exposure within the proteome as translation was dysregulated, leading to a significant decrease in protein synthesis. Completion of this study has given greater insight into the molecular mechanisms governing the response to short term Cd insult and how dysregulation of the Sir2p-Hcm1p interaction can lead to increasing stress within the cell, resulting in the disruption of many pathways.

DOI

https://doi.org/10.57709/36973275

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