Author ORCID Identifier
0000-0002-4547-9663
Date of Graduation
12-2023
Document Type
Dissertation (PhD)
Program Affiliation
Genetics and Epigenetics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Mark T. Bedford; PhD
Committee Member
David G. Johnson, PhD
Committee Member
Manu M. Sebastian, DVM, PhD
Committee Member
Min Gyu Lee, PhD
Committee Member
Taiping Chen, PhD
Committee Member
Laura Beretta, PhD
Abstract
Arginine methylation is an essential post-translational modification (PTM) in cells. Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme that catalyzes symmetric dimethyl arginine (SDMA) and requires methylosome protein 50 (MEP50) for stability and enzymatic activity which are necessary for life and development. Effector proteins bind different types of PTM’s to facilitate signaling. Staphylococcal nuclease Tudor domain containing 1 (SND1) is an effector that specifically binds SDMA via its single C-terminal Tudor domain. Both SND1 and PRMT5 have been implicated in hepatocellular carcinoma (HCC). SND1 has been confirmed as a driver of HCC using genetically engineered mouse models (GEMMs), though, it remains unknown if loss of SND1 or its methyl reading ability can protect against HCC formation. PRMT5 has been reported as upregulated in many cancers and may predispose hepatocytes to develop HCC. However, it remains to be determined if Prmt5 overexpression (OE) alone is sufficient to drive HCC. This work utilizes three new GEMMs, namely a Snd1 KO, Snd1 Tudor domain mutant (KI), and tissue specific Prmt5 OE mouse, to answer these key questions: 1) Does loss of SND1 or its methyl binding ability impact tumorigenesis? and 2) Does Prmt5 OE predispose mice to develop HCC? We characterize and validate each of these GEMMs and use a high penetrance HCC assay to determine the role of this effector/writer pair to begin answering these questions. First, the Snd1 KO and KI mice reveal a Tudor domain independent “small” phenotype and reveal distinct transcriptional control by SND1 and its Tudor domain. Snd1 KO and KI mice are further hepatoprotected against carcinogen-induced HCC. Next, Prmt5 OE mice reveal important insight into PRMT5 biology and suggest that elevated PRMT5 levels do not correlate with elevated SDMA levels. Carcinogenesis studies using two cancer-inducing models further strengthen our understanding of these processes. This work provides important information about the SND1/PRMT5 axis in liver cancer and how this axis may be a viable target for treating HCC.
Keywords
Hepatocellular Carcinoma, PRMT5, Arginine methylation, SND1, HCC, reader, writer, epigenetics