The role of the G-Quadruplex helicase, DHX36/G4R1, in lymphoma utilizing novel transgenic mice

Access to thesis restricted until 07/2023.Nearly 700 thousand people each year succumb to cancer in the United States alone, making the identification of novel therapeutic targets an urgent need. Cancer is driven, in part, by oncogenes which promote cancer progression when mutated or overexpressed. G-quadruplex (G4) DNAs are dynamic, guanine-rich, nucleic acid structures that act as regulatory transcriptional “dimmer switches”. Of note, genes that promote cell proliferation and survival (i.e., oncogenes) are more likely to contain G4 sequences, while genes that suppress cell proliferation and survival (i.e., tumor suppressor genes) are depleted of G4s. Therefore, G4s represent an epigenetic feature that generally distinguishes oncogenes from tumor suppresser genes. A key master regulator of oncogene expression is the G4 helicase, DHX36 (aliases: G4R1 and RHAU). DHX36 functions like an oncogene by stimulating the expression of G4- containing oncogenes, including c-MYC. DHX36 is overexpressed in most tumor types, which is significantly correlated with reduced patient survival. The oncogenic role of DHX36-overexpression in animal models has not been evaluated. I hypothesize that Dhx36 overexpression increases oncogene expression, initiates tumorigenesis, and increases tumor growth. Here I validate, for the first time, a novel Dhx36- overexpression model. I have assessed this model for tumor initiation and have begun determining the role of Dhx36-overexpression on oncogene expression. Our findings suggest an overexpression of Dhx36 suppresses the initiation of tumorigenesis. I expect that these effects will be driven, in part, due to increased oncogene expression. Completion of this work will contribute to the basic understanding of lymphoma initiation, lymphoma progression, and the rational development of DHX36-targeted therapeutics.Thesis (M.S.