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Spardy, Nicole Ann (2009) THE HUMAN PAPILLOMAVIRUS TYPE 16 E7 (HPV-16 E7) ONCOPROTEIN AND THE HOST CELL DNA DAMAGE RESPONSE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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High-risk human papillomaviruses (HPVs), such as HPV-16, are the etiological agents of squamous cell carcinomas (SCCs) of the anogenital tract and a subset of oropharyngeal cancers. High-risk HPVs encode two oncoproteins, E6 and E7, which promote unscheduled host cell proliferation by targeting the p53 and pRB tumor suppressor proteins, respectively. HPV-16 E7 has been shown to stimulate structural chromosomal instability and DNA breakage. These findings raise several important questions. First, how does HPV-16 E7 induce DNA damage? Second, what are the precise consequences of HPV-16 E7-induced DNA damage for host cell genomic integrity, and lastly, how do HPV-16 E7-expressing cells maintain proliferation despite activated DNA damage checkpoints? Here, we show that HPV-16 E7 activates the Fanconi Anemia (FA) pathway, a branch of the host cell DNA damage response that primarily responds to stalled DNA replication forks. Importantly, we show that HPV-16 E7 expression in FA-deficient cells accelerates the formation of structural chromosomal alterations, which may help to explain the heightened susceptibility of FA patients to HPV-associated tumors. However, we also provide evidence that HPV-16 E7-induced FA pathway activation in FA-proficient cells may contribute to evasion of anti-proliferative host cell barriers by promoting alternative lengthening of telomeres (ALT). Finally, we demonstrate that HPV-16 E7 circumvents DNA damage checkpoint control and promotes aberrant mitotic entry by increasing the proteolytic turnover of claspin, which plays a role in the ATR/CHK1-mediated replication stress response. Collectively, our results underscore that HPV-16 E7 interferes with host cell genome integrity by inducing DNA replication stress. The detrimental effects of HPV-16 E7 on the genomic integrity of host cells with a deficient FA pathway support the notion that this DNA damage response pathway is crucial to prevent HPV-16 E7-induced genomic instability and malignant progression. However, we also provide evidence that HPV-16 E7 can exploit the FA pathway to promote cellular immortalization. Future experiments to explore these events for cancer therapy and/or prevention are warranted.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Spardy, Nicole Annnas32@pitt.eduNAS32
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDuensing, Stefanduensing@pitt.eduDUENSING
Committee MemberPipas, Jamespipas@pitt.eduPIPAS
Committee MemberNiedernhofer, Lauraniedernh@pitt.eduNIEDERNH
Committee MemberDeLuca, Nealndeluca@pitt.eduNDELUCA
Committee MemberKhan, Saleemkhan@pitt.eduKHAN
Date: 7 August 2009
Date Type: Completion
Defense Date: 14 May 2009
Approval Date: 7 August 2009
Submission Date: 5 August 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: DNA damage; genomic instability; Human papillomavirus
Other ID:, etd-08052009-121401
Date Deposited: 10 Nov 2011 19:57
Last Modified: 15 Nov 2016 13:48


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