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Viruses 2016, 8(6), 175; doi:10.3390/v8060175

DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication

1
VCU Philips Institute for Oral Health Research, Department of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University School of Dentistry, Richmond, VA 23298, USA
2
VCU Massey Cancer Center, Richmond, VA 23298, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Joanna Parish
Received: 26 May 2016 / Revised: 14 June 2016 / Accepted: 16 June 2016 / Published: 22 June 2016
(This article belongs to the Section Animal Viruses)
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Abstract

Human papillomaviruses (HPVs) are causative agents in almost all cervical carcinomas. HPVs are also causative agents in head and neck cancer, the cases of which are increasing rapidly. Viral replication activates the DNA damage response (DDR) pathway; associated proteins are recruited to replication foci, and this pathway may serve to allow for viral genome amplification. Likewise, HPV genome double-strand breaks (DSBs) could be produced during replication and could lead to linearization and viral integration. Many studies have shown that viral integration into the host genome results in unregulated expression of the viral oncogenes, E6 and E7, promoting HPV-induced carcinogenesis. Previously, we have demonstrated that DNA-damaging agents, such as etoposide, or knocking down viral replication partner proteins, such as topoisomerase II β binding protein I (TopBP1), does not reduce the level of DNA replication. Here, we investigated whether these treatments alter the quality of DNA replication by HPV16 E1 and E2. We confirm that knockdown of TopBP1 or treatment with etoposide does not reduce total levels of E1/E2-mediated DNA replication; however, the quality of replication is significantly reduced. The results demonstrate that E1 and E2 continue to replicate under genomically-stressed conditions and that this replication is mutagenic. This mutagenesis would promote the formation of substrates for integration of the viral genome into that of the host, a hallmark of cervical cancer. View Full-Text
Keywords: papillomaviruses; cancer; replication; etoposide; integration; E1; E2; TopBP1; HPV papillomaviruses; cancer; replication; etoposide; integration; E1; E2; TopBP1; HPV
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MDPI and ACS Style

Bristol, M.L.; Wang, X.; Smith, N.W.; Son, M.P.; Evans, M.R.; Morgan, I.M. DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication. Viruses 2016, 8, 175.

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