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The Role of HUWE1 in DNA replication and genome stability in multiple myeloma Jonathan Morgan (8037426) PUREID: 362669802 Multiple Myeloma E3 Ligase HUWE1 replication stress genome instability <p>Multiple Myeloma (MM) is ahaematological malignancy of terminally differentiated B cells. Despitesignificant advances in treatment options, development of resistance and toxicside effects are still a major clinical problem, and the disease remains incurable.This highlights the need for a deeper understanding of the pathogenesis of MMand the identification of novel therapeutic targets. Dysregulated expression ofthe E3 ligase HUWE1 has been reported in MM and HUWE1 has subsequently beenidentified as a potential therapeutic target. Recent genomic studies alsouncovered HUWE1 as a novel mutational driver gene in MM, further implicatingthe E3 ligase in MM pathogenesis. HUWE1 is known to regulate a myriad ofproteins involved in key cellular processes including DNA repair, replicationand apoptosis. The aim of this study was to investigate the role of HUWE1 inreplication and DNA damage response (DDR) pathways in MM. </p><p>Expression of HUWE1 wasdemonstrated to increase in a stepwise manner across plasma cell dyscrasias,and high expression in MM patients was found to confer a shorter overallsurvival. Knockdown of HUWE1 using shRNA technology demonstrated significantlyreduced cellular proliferation compared to the control which was underpinned bya S phase arrest. Replication proteins were identified as a novel substrate ofHUWE1, which was found to catalyse the polyubiquitination of the replicationprotein. Further investigation found that this HUWE1-mediated ubiquitinationwas essential for loading of these proteins to sites of DNA damage induced byreplicative stress and ultimately resulted in a DNA damage repair defect. </p><p>Another area of this studyfocused on delineating the functional consequences of clinically relevant HUWE1mutations which are observed in approximately 5% of MM patients. Patients witha HUWE1 mutation were observed to have significantly higher number ofco-occurrent non-synonymous and somatic mutations. Analysis of a panel of MMcell lines with wild-type or mutant HUWE1, identified a similar phenotype inwhich HUWE1 mutant cell lines exhibited higher mutation rates as determined bythe PIG-A gene mutation assay and increased incidence of micronuclei formation,two characteristics indicative of genomic instability. This loss of genomestability was determined to be underpinned by a dampened DNA repair response. </p><p>This work outlines a clear rolefor HUWE1 in genome stability and highlights that exploitation of thereplication stress response may represent a therapeutic vulnerability for MM patientswith a HUWE1 mutation.</p><br> 2026-10-01T17:04:28Z Text Thesis 10.17034/32633304.v1 https://figshare.com/articles/thesis/The_Role_of_HUWE1_in_DNA_replication_and_genome_stability_in_multiple_myeloma/32633304 All Rights Reserved