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Restricted Access Thesis

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First Advisor

Anne McBride


The opportunistic fungal pathogen Candida albicans causes mild and severe diseases when not suppressed by the immune system, yet its mechanisms of gene expression remain poorly understood, particularly beyond the level of transcription. However, post-transcriptional regulation has recently been implicated in C. albicans drug resistance and fungal pathogenesis. Alternative splicing (AS) is one such post-transcriptional mechanism that greatly expands eukaryotic protein diversity and enables important regulatory functions. While associative relationships between AS and pathogenesis have been documented in C. albicans, the mechanisms through which introns are retained or removed remain unclear. The SR-like RNA binding protein 1 (Slr1) serves critical roles in C. albicans growth, filamentation, and virulence, and accumulating studies evince its role as a splicing factor. As an SR-like protein, Slr1 bears an RS domain whose phosphorylation likely influences Slr1 localization, expression levels, protein-protein interactions, and yet undetermined roles in gene expression. Given that phosphorylation of SR and SR-like proteins is required for most steps in pre-mRNA splicing, I tested the impact of blocking or mimicking the phosphorylation of Slr1 using mutational approaches. Intriguingly, structural modifications that mimic both the hyper- and hypophosphorylation of Slr1 are associated with reduced splicing of its own transcript, supporting a model in which Slr1 negatively autoregulates its protein levels through a phosphorylation-dependent mechanism involving the splicing of its pre-mRNA. This study demonstrates a novel mechanism of post-transcriptional regulation in C. albicans that enables future research into its gene expression, growth, and pathogenesis.


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