A Study of The Snd1/Prmt5 Axis In Liver Cancer By Genetic Mouse Models

<p>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 <em>Prmt5 </em>overexpression (OE) alone is sufficient to drive HCC. This work utilizes three new GEMMs, namely a <em>Snd1 KO</em>, <em>Snd1 </em>Tudor domain mutant (<em>KI)</em>, and tissue specific <em>Prmt5 OE</em> mouse, to answer these key questions: 1) Does loss of SND1 or its methyl binding ability impact tumorigenesis? and 2) Does <em>Prmt5</em> <em>OE</em> 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 <em>Snd1 KO</em> and <em>KI</em> mice reveal a Tudor domain independent “small” phenotype and reveal distinct transcriptional control by SND1 and its Tudor domain. <em>Snd1</em> <em>KO</em> and <em>KI</em> mice are further hepatoprotected against carcinogen-induced HCC. Next, <em>Prmt5</em> <em>OE</em> 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Wright, Tanner
• <p>0000-0002-4547-9663</p>

Contributors dc:contributor

• Mark T. Bedford; PhD
• David G. Johnson, PhD
• Manu M. Sebastian, DVM, PhD

• Hepatocellular Carcinoma
• PRMT5
• Arginine methylation
• SND1
• HCC
• reader
• writer
• epigenetics
• Genetics
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1309

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2366