Yeast Ess1, a Conserved PPlase Essential for Mitosis

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DESCRIPTION (APPLICANT'S ABSTRACT): The long-term goal is to understand how prolyl-isomerases (PPIases) control important cellular processes such as transcription and mitosis. These enzymes catalyze the cis/trans isomerization of the peptide bond that precedes the cyclic amino acid proline. This conformational change is thought to be important for proper folding of proteins and control of their activity. PPIases are found in all organisms, and are best known because they are the targets of immunosuppressive and antifungal drugs. However, their normal function in cells is not understood, since most can be removed by gene deletion in their respective organism without observable consequences. There is one exception, however, a PPIase called Ess 1 that is required for growth in the yeast, Saccharomyces cerevisiae. Ess 1 and its human homolog, Pin 1, are implicated in cell cycle confrol. Recent discoveries show that Ess 1 interacts physically and genetically with the carboxy-terminal domain (CTD) of RNA polymerase II, suggesting a role in transcription of cell cycle genes. This study will take advantage of the essential nature of Ess 1 and the power of yeast genetics to elucidate the Ess1 pathway. The main focus will be to understand the role of Essi in transcription. Specifically, the aims are: (1) to define genetic interactions between the ESS1 gene and genes that are known to be important for transcription, (2) to discover genes whose transcription depends on Ess1 and that control cell cycle progression through mitosis, (3) to combine the use of yeast genetics with biochemistry to study how Ess1 binds the CTD, with the goal of determining how Ess1 controls RNA polymerase II function, and finally, (4) to examine the importance of Ess1 for virulence in pathogenic fungi, with the eventual goal of developing antifungal drugs that inhibit Ess1 function.