Dacus, Dalton2022-04-182022-04-182022-05-01https://hdl.handle.net/2097/42179Beta genus human papillomaviruses ([Beta]-HPV) are associated with the development of cutaneous squamous cell carcinomas (cSCC) by destabilizing the genome. In vitro and in vivo studies indicate the [Beta]-HPV E6 and E7 proteins act as co-factors with ultraviolet radiation (UV) to cause genome destabilization. However, the E6 protein from [Beta]-HPV type 8 (8 E6) induces tumor formation in mice without UV exposure, but the mechanisms driving carcinogenesis are unclear. In this dissertation, we investigated UV-independent mechanisms of HPV8 E6-induced genome destabilization. In silico screens validated by cell line characterization showed that 8 E6 deregulated the Hippo pathway by destabilizing the histone acetyltransferase, p300. Hippo pathway disruption increased cell proliferation and attenuated cell death in response to failed cytokinesis. While 8 E6 alone was unable to promote long-term proliferation after cytokinesis failure, we demonstrated that 8 E6 combined with TERT expression rescued long-term proliferation. However, this resulted in increased genomic instability in the form of ploidy changes. Furthermore, we showed 8 E6 decreased the abundance of anaphase bridge resolving helicase, Bloom syndrome protein (BLM). The diminished BLM was associated with increased segregation errors and micronuclei. 8 E6 reduced antiproliferative responses to micronuclei and time-lapse imaging revealed 8 E6 promoted cells with micronuclei to complete mitosis. Finally, whole-genome sequencing demonstrated that 8 E6 induced a mutational phenomenon known as chromothripsis, in 9 chromosomes. Overall, the findings from my dissertation provide insight into the processes by which 8 E6 induces genome instability in the absence of UV exposure.en-US© the author. This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).http://rightsstatements.org/vocab/InC/1.0/Human papillomavirusCancerChromothripsisp300HPV8Dissertation