The long-term goal is to understand how peptidyl-prolyl isomerases (PPIases) control important cellular processes such as transcription and mitosis. PPIases catalyze the cis/trans isomerization of the peptide bond that precedes the cyclic amino acid proline. Prolyl-isomerization results in conformational changes that affect the folding of newly synthesized proteins and regulates the activity of mature proteins. PPIases are found in all organisms, and are best known because they are the targets of immunosuppressive drugs. However, their normal function in cells is poorly understood, in part, because most can be removed by gene deletion in their respective organism without observable consequences. One exception is a PPIase called Ess1, which is essential for growth in the yeast, Saccharomyces cerevisiae. Ess1 and its human homolog, Pin1, are implicated in transcription regulation and cell cycle control. Ess1 interacts physically and genetically with the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II. Ess1 is proposed to isomerize the CTD and thereby control the transition between multiple, discrete stages of transcription and mRNA processing. Loss of Ess1 causes cells to undergo mitotic arrest, perhaps due to defects in transcription of key cell cycle genes. This study will focus on determining the mechanism by which Ess1 controls transcription and its importance for global gene expression. It will also explore the structural basis for targeting of Ess1 in pathogenic yeast for clinical applications. Specifically, the aims are to: (1) Use biochemical and molecular approaches to determine the mechanism by which Ess1 regulates RNA polymerase II activity, (2) Use genetic and genomic approaches to identify genes that require Ess1, (3) Use structure and function analysis to examine enzyme-substrate interactions by Candida albicans Ess1, with the long-term goal of exploiting key differences between the fungal and human enzymes for development of antifungal drugs. Public Health Relevance: The study of Ess1 in fungi will be important for our understanding of the human counterpart, Pin1, which has been associated with cancers and neurodegenerative disorders. The results may also establish Ess1 as a new drug target for treatment of patients with life- threatening fungal infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055108-12
Application #
7786254
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Tompkins, Laurie
Project Start
1997-07-01
Project End
2011-01-02
Budget Start
2010-04-01
Budget End
2011-01-02
Support Year
12
Fiscal Year
2010
Total Cost
$152,727
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
Hanes, Steven D (2015) Prolyl isomerases in gene transcription. Biochim Biophys Acta 1850:2017-34
Allepuz-Fuster, Paula; Martínez-Fernández, Verónica; Garrido-Godino, Ana I et al. (2014) Rpb4/7 facilitates RNA polymerase II CTD dephosphorylation. Nucleic Acids Res 42:13674-88
Hanes, Steven D (2014) The Ess1 prolyl isomerase: traffic cop of the RNA polymerase II transcription cycle. Biochim Biophys Acta 1839:316-33
Atencio, David; Barnes, Cassandra; Duncan, Thomas M et al. (2014) The yeast Ess1 prolyl isomerase controls Swi6 and Whi5 nuclear localization. G3 (Bethesda) 4:523-37
Samaranayake, Dhanushki; Atencio, David; Morse, Randall et al. (2013) Role of Ess1 in growth, morphogenetic switching, and RNA polymerase II transcription in Candida albicans. PLoS One 8:e59094
Ma, Zhuo; Atencio, David; Barnes, Cassandra et al. (2012) Multiple roles for the Ess1 prolyl isomerase in the RNA polymerase II transcription cycle. Mol Cell Biol 32:3594-607
Cosgrove, Michael S; Ding, Ye; Rennie, William A et al. (2012) The Bin3 RNA methyltransferase targets 7SK RNA to control transcription and translation. Wiley Interdiscip Rev RNA 3:633-47
Samaranayake, Dhanushki P; Hanes, Steven D (2011) Milestones in Candida albicans gene manipulation. Fungal Genet Biol 48:858-65
McNaughton, Lynn; Li, Zhong; Van Roey, Patrick et al. (2010) Restricted domain mobility in the Candida albicans Ess1 prolyl isomerase. Biochim Biophys Acta 1804:1537-41
Singh, Navjot; Ma, Zhuo; Gemmill, Trent et al. (2009) The Ess1 prolyl isomerase is required for transcription termination of small noncoding RNAs via the Nrd1 pathway. Mol Cell 36:255-66

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