Beta human papillomavirus E6: a menace to genomic integrity
dc.contributor.author | Dacus, Dalton | |
dc.date.accessioned | 2022-04-18T13:50:09Z | |
dc.date.available | 2022-04-18T13:50:09Z | |
dc.date.graduationmonth | May | en_US |
dc.date.issued | 2022-05-01 | |
dc.date.published | 2022 | en_US |
dc.description.abstract | Beta 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 |
dc.description.advisor | Nicholas A. Wallace | en_US |
dc.description.degree | Doctor of Philosophy | en_US |
dc.description.department | Department of Biology | en_US |
dc.description.level | Doctoral | en_US |
dc.description.sponsorship | Johnson Cancer Research Center National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health P20 GM130448 and P20 GM103418 Department of Defense CMDRP PRCRP CA160224 | en_US |
dc.identifier.uri | https://hdl.handle.net/2097/42179 | |
dc.language.iso | en_US | en_US |
dc.subject | Human papillomavirus | en_US |
dc.subject | Cancer | en_US |
dc.subject | Chromothripsis | en_US |
dc.subject | p300 | en_US |
dc.subject | HPV8 | en_US |
dc.title | Beta human papillomavirus E6: a menace to genomic integrity | en_US |
dc.type | Dissertation | en_US |
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