Cervical cancer: An unanticipated consequence of high-risk human papillomavirus infection

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dc.contributor.author Walterhouse, Stephen James
dc.date.accessioned 2018-08-09T14:47:20Z
dc.date.available 2018-08-09T14:47:20Z
dc.date.issued 2018-08-01 en_US
dc.identifier.uri http://hdl.handle.net/2097/39118
dc.description.abstract Cancer is not a single story, but rather numerous often interwoven tales, each with its own characters and progression. In the case of human papillomavirus (HPV) induced cervical cancer (CaCx), the narrative is about the relationship between virus and host, with the consequences of evolution’s shortsightedness driving the plot. Along with the increased proliferative state characteristic of cancer, cells experience frequent, inaccurate replication and replication stresses (ex. DNA damage and nucleotide starvation). To prevent replication fork stall and collapse generated by these stresses, the cell employs translesion synthesis (TLS). Notably, most of the genes in this pathway are upregulated in CaCx; however, the key protein polymerase eta is not. We have observed that upregulation in this pathway is complicated. It occurs at numerous levels, increasing both mRNA and protein abundance. This research further dissects how TLS upregulation occurs. Data shows that in CaCx-derived cell lines, the stability of some TLS proteins is increased, while the stability of other TLS proteins is unchanged. The increased proliferation, typical of these cell lines, cannot account for the enhanced stability. Despite increased TLS protein stability, these cells fail to adequately activate TLS increasing the risk of DNA damage. Genomic instability is a driving factor in HPV genome integration that prevents viral propagation and leads to cell transformation. It also raises mutagenesis rates, likely creating a selective pressure for tolerating failed TLS. The elevated mutation rate known to be associated with failed TLS could also provide a mechanism for acquired resistance to the drugs commonly used to treat CaCx. Changes in protein abundance are routinely used as biomarkers that can lead to the improved outcomes associated with early cancer detection. Elevated TLS protein could be leveraged to ensure cervical cancers are detected during Stage 1, when the 5-year survival rate is 80-90%, rather than at Stage IV, when the rate dips to around 15%. en_US
dc.description.sponsorship Kansas State University Jonson Cancer Research Center The Les Clow Family Kansas Idea Network of Biomedical Research Excellence en_US
dc.language.iso en_US en_US
dc.subject Human papilloma virus en_US
dc.subject Evolution en_US
dc.subject Translesion synthesis en_US
dc.subject Protein stability en_US
dc.subject Cervical cancer en_US
dc.title Cervical cancer: An unanticipated consequence of high-risk human papillomavirus infection en_US
dc.type Thesis en_US
dc.description.degree Master of Science en_US
dc.description.level Masters en_US
dc.description.department Division of Biology en_US
dc.description.advisor Nicholas A. Wallace en_US
dc.date.published 2018 en_US
dc.date.graduationmonth August en_US

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