Investigating the Effects of FUS and EWSR1 Proteins on T7 and RNA POL II Transcription
Author
WIELAND, DANIEL ROBERTIssue Date
2021Advisor
Schwartz, Jacob
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The University of Arizona.Rights
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.Abstract
Fused in Sarcoma (FUS), Ewing Sarcoma (EWSR1), and TATA-Box Binding Protein Associated Factor 15 (TAF15) make up the ubiquitously expressed FET family of proteins, which plays a large role in regulating genomic integrity, nucleic acid metabolism, and transcription. In FUS, mutations are known to result in neurodegenerative disorders such as frontotemporal dementia and amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. With EWSR1, a chromosomal translocation event with the transcription factor FLI1 results in the fusion protein EWS-FLI1, which is responsible for the titular Ewing sarcoma, an aggressive pediatric bone cancer. Placing FUS in a novel, in-vitro environment with the bacteriophage RNA polymerase T7 revealed an unexplored mechanism of RNA upregulation through the prevention of DNA:RNA hybrids (R-loops), a triple-stranded nucleic acid structure that forms during transcription. In Ewing Sarcoma and control cell lines, knockdowns and transfections have also identified how EWS-FLI1 drive tumorigenesis through the upregulation and downregulation of thousands of genes as identified through RNA sequencing. Here we combined a computational and biochemical approach to study how EWS-FLI1 influences transcription to promote oncogenesis, and how FUS promotes transcription through via DNA:RNA hybrids at the molecular level.Type
Electronic thesistext
Degree Name
B.S.Degree Level
bachelorsDegree Program
BiochemistryHonors College