Award Date

12-15-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Committee Member

Gary Kleiger

Second Committee Member

Hui Zhang

Third Committee Member

Ernesto Abel-Santos

Fourth Committee Member

Kelly Tseng

Number of Pages

159

Abstract

Protein degradation is a fundamental process required for maintaining cellular homeostasis in eukaryotic organisms. In humans, distinct cell types exhibit unique proteomic landscapes that are dynamically balanced by the continual synthesis and degradation of proteins. The timely removal of damaged, misfolded, or old proteins is essential to permit new protein synthesis and to ensure proper cellular function.

Central to this regulatory network is ubiquitylation, a highly conserved posttranslational modification system that governs protein stability and function across all eukaryotic cells. Through the covalent attachment of ubiquitin molecules to protein substrates, this system modulates a broad range of biological processes, including cell cycle progression, differentiation, immune response, DNA repair, and vesicle trafficking. Substrates can be tagged with a single ubiquitin (“priming”) or decorated with polyubiquitin chains (“chaining”), whose length and linkage topology dictate diverse signaling outcomes, from proteasomal degradation to altered subcellular localization or activity modulation.

Among the hundreds of E3 ubiquitin ligases encoded in the human genome, cullin-RING ubiquitin ligases (CRLs) represent the largest and most functionally diverse subfamily. CRLs assemble into modular complexes capable of recognizing and regulating thousands of distinct substrates, collectively accounting for nearly 20% of all protein turnover within the cell. Their central role in protein homeostasis links them to a range of human diseases, including cancer, neurodegeneration, and immune disorders, rendering CRLs attractive targets for therapeutic intervention. Despite their biological significance, the molecular principles that determine substrate specificity, dynamic assembly, and regulatory mechanisms of CRLs remain incompletely understood.

This dissertation aims to elucidate key mechanistic aspects of CRL function, particularly focusing on their coordination with ubiquitin-carrying enzymes that form physiological partnerships within the cell. By dissecting these interactions, this work seeks to contribute to a deeper understanding of the “CRL code” that governs selective protein degradation, with implications for both fundamental cell biology and the development of targeted therapeutics.

Controlled Subject

Proteolysis; Homeostasis; Ubiquitin

Disciplines

Biochemistry | Biochemistry, Biophysics, and Structural Biology | Life Sciences

File Format

PDF

File Size

12700 KB

Degree Grantor

University of Nevada, Las Vegas

Language

English

Rights

IN COPYRIGHT. For more information about this rights statement, please visit http://rightsstatements.org/vocab/InC/1.0/

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Biochemistry Commons

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