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.
Highlights
Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that cause a variety of human diseases, including, but not limited to, cervical cancer and head and neck cancers [1,2].HPV16 is the most prevalent genotype in both cervical and head and neck cancers [2]
The results demonstrate that elimination of TopBP1 or treatment of cells with etoposide did not affect the levels of DNA replication as reported previously [31,32], but dramatically increased the mutation frequency
DNA replication (Figure 1), we investigated the effects of Small interfering RNA (siRNA) TopBP1
Summary
Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that cause a variety of human diseases, including, but not limited to, cervical cancer and head and neck cancers [1,2]. The results demonstrate that E1 and E2 proteins have a remarkable capacity to replicate under conditions of genomic stress and that this replication is error prone under such conditions This error-prone replication would promote double-stranded DNA breaks in the viral genome that would provide substrates for the integration of the viral genome into that of the host. Our results suggest that any therapy targeting HPV DNA replication should be investigated for the effect on the quality of that replication. This can be done using the simple blue-white screen employed in this report
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