Doctor of Philosophy
Anatomy and Cell Biology
Regulation of gene expression under stress conditions involves chromatin remodeling through post-translational modification of histones. One of these modifications, acetylation of lysine residues, regulates transcription initiation and is linked to a variety of essential cellular processes including cell cycle control, DNA repair, and importantly, activation of cellular stress response pathways. Dysregulation of histone acetylation has been observed in many stress-related diseases such as inflammatory diseases, cancer, neurodegenerative disorders, and fungal infections. Tra1 is the only essential component of both the highly conserved SAGA and NuA4 histone acetyltransferase (HAT) complexes that are responsible for acetylation of histones and other proteins. Tra1 has been shown to be involved in the regulation of stress response pathways; however, the underlying mechanisms remain unclear. Huntington’s disease (HD) is a neurodegenerative disease caused by the aberrantly expanded polyglutamine (polyQ) repeats within the gene encoding the Huntingtin protein (Htt), leading to misfolding and aggregation of the mutant Htt. Defect in misfolded protein stress responses is a hallmark of HD. Thus, I sought to investigate how Tra1 orchestrates the transcriptional responses to toxic misfolded polyQ expansions. First, I developed an optimized yeast model of HD to study the effects of Tra1 on polyQ toxicity. I found that polyQ expansions impair the assembly of the Tra1-containing SAGA HAT complex. This correlates with loss of Tra1/SAGA function that exacerbates polyQ toxicity. Furthermore, polyQ expansions lead to increased expression of TRA1, revealing a compensatory feedback mechanism. Interestingly, deletion of SFP1, a transcription regulator downstream of TORC1, abolished TRA1 upregulation upon polyQ expression. Thus, I identified a novel link between Tra1 and TORC1 signaling. Moreover, I showed that the increased sensitivity to heat stress in cells expressing expanded polyQ is rescued by an osmotic stabilizer sorbitol, suggesting that the defect can be traced back to the cell wall integrity. Considering that Tra1 is vital to maintain cell wall integrity and activation of the heat shock response, it appears that impaired Tra1/SAGA functions could underlie the dysregulation of these stress responses in the yeast model of HD. Finally, because of its essential role in cell wall maintenance and calcium homeostasis (two targets of antifungal drugs), Tra1 emerges as a rationale target for pathological yeast infections. Indeed, I found that cells expressing a mutant tra1 allele showed increased sensitivity to antifungal drugs. Overall, my graduate work helps characterize the global role of Tra1 in protein homeostasis and define its potential as a therapeutic target for stress-related human diseases.
Summary for Lay Audience
Cells respond to environmental insults by remodeling their genome. Cells require critical transcriptional machinery to regulate the expression of specific genes in response to different stressors. Impaired cellular stress response pathways can lead to accumulation of toxic misfolded proteins and major cellular dysfunctions, which are a hallmark of several human disorders from neurodegeneration to our ability to fight fungal infection. Hyperactivation of cellular stress responses, on the other hand, can cause drug resistance in cancer and lead to emergence of drug resistant microorganisms. Therefore, it is crucial to investigate the regulation of cellular stress responses and their implication in stress-related diseases. Using the budding yeast as an experimental model, my thesis explores how cells respond to stress in two major health problems: Huntington’s Disease and yeast resistance to antifungal drugs. While these two issues appear quite distinct, my work established that a single protein, Tra1, plays a pivotal role in controlling how cells modulate gene expression under stress conditions linked to these pathologies. Therefore, understanding the crucial role of Tra1 in cellular stress responses will provide better insights into the pathogenesis and therapies of stress-related disorders.
Jiang, Yuwei, "The Role of Tra1 in Cellular Stress Responses in Yeast: Implications for Human Diseases" (2019). Electronic Thesis and Dissertation Repository. 6513.
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