Determining the impact of WDR5 on the ability of N-MYC to bind chromatin

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Bumpous, Leigh
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Middle Tennessee State University
Neuroblastoma is a pediatric cancer of the nervous system, and high-risk patients are known to have poor prognoses. N-MYC is an oncoprotein transcription factor that is commonly overexpressed through gene amplification in high-risk pediatric neuroblastoma cases. In order for N-MYC to drive oncogenesis, it must first bind chromatin to regulate expression of target genes linked to cancer functions. The chromatin regulator WDR5 has been shown to directly bind the c-MYC family member and facilitate recruitment of MYC to chromatin at genes involved in cancer-regulated functions such as protein synthesis, cell cycle progression, proliferation, and apoptosis. However, whether this is true for N-MYC in neuroblastoma remains unknown. During my thesis work, we identified a conserved core set of binding sites known to be bound by both N-MYC and WDR5. Then, to investigate the impact of WDR5 on the ability of N-MYC to bind chromatin, multiple approaches to interrupt the N-MYC-WDR5 interaction, such as a dTAG-directed degradation system and a Tet-on inducible genetic system, were used in the engineered neuroblastoma cell lines. Results demonstrate that when N-MYC was unable interact with WDR5, N-MYC binding to chromatin was specifically decreased at sites co-bound by N-MYC and WDR5. Our findings have implications for high-risk neuroblastomas and pave the way for novel treatment avenues involving inhibition of the N-MYC-WDR5 interaction as a new approach to block N-MYC function.
Chromatin, MYC, N-MYC, Neuroblastoma, Oncogene, WDR5, Oncology, Molecular biology, Cellular biology