The Human Papillomavirus E7 Induces Re-replication in Response to DNA Damage.

ArticleinJournal of Virology 87(2) · November 2012with17 Reads
DOI: 10.1128/JVI.02038-12 · Source: PubMed
Human papillomavirus (HPV) infection is necessary but not sufficient for cervical carcinogenesis. Genomic instability caused by HPV allows cells to acquire additional mutations required for malignant transformation. Genomic instability in the form of polyploidy has been demonstrated to play an important role in cervical carcinogenesis. We have recently found that HPV-16 E7 oncogene induces polyploidy in response to DNA damage; however, the mechanism is not known. Here we present evidence demonstrating that HPV-16 E7-expressing cells have an intact G2 checkpoint. Upon DNA damage, HPV-16 E7-expressing cells arrest at the G2 checkpoint and then undergo rereplication, a process of successive rounds of host DNA replication without entering mitosis. Interestingly, the DNA replication initiation factor Cdt1, whose uncontrolled expression induces rereplication in human cancer cells, is upregulated in E7-expressing cells. Moreover, downregulation of Cdt1 impairs the ability of E7 to induce rereplication. These results demonstrate an important role for Cdt1 in HPV E7-induced rereplication and shed light on mechanisms by which HPV induces genomic instability.
    • "This function is countered by HPV E6 mediated degradation of p53 via activation of the ubiquitin ligase E6AP [8,13]. E6 and E7 act in concert to inhibit apoptosis, promote unrestrained cell proliferation, and play key roles in the promotion of genomic instability [2,8,14,15], all critical factors in HPV-mediated carcinogenesis. E6 and E7 cooperate to promote chromosomal segregation errors and aneuploidy [15] while E7 induces centrosome synthesis via CDK2 activity [16]. "
    [Show abstract] [Hide abstract] ABSTRACT: Human papillomaviruses (HPVs) are small double-stranded DNA viruses that pose significant public health concerns as the causative agent of approximately 5% of worldwide cancers. The HPV oncogenes E6 and E7 play key roles in carcinogenesis. In the last 15years there has been a significant increase in the incidence of HPV-related head and neck cancers arising primarily in the oropharynx. Patients with HPV-positive head and neck cancers (HNCs) have a significantly improved prognosis compared to those with HPV-negative disease. In this review we will discuss data suggesting how HPV oncogenes modulate both the intrinsic radiation sensitivity of HNCs and also have important effects upon the tumor microenvironment. Together, these findings contribute to the improved outcomes seen in patients with HPV-positive HNC.
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    • "For Western blot analysis, protein were analyzed as described [36]. The following antibodies were used: Dyrk1B (Cell Signaling Technology), β-Tubulin (Sigma, T5168), p27 (Santa Cruz, sc-528), p27 phospho S10 (Abcam, ab62364), p27 phospho T198 (R&D Systems, AF3994), FLAG (Sigma, F1804), HA (Santa Cruz, sc- 7392), HPV16 E7 (Santa Cruz, sc-6981), IRDye 800CW goat anti-mouse IgG (Licor, 926-32210), IRDye 800CW goat anti-rabbit IgG (Licor, 926-32211). "
    [Show abstract] [Hide abstract] ABSTRACT: The high-risk human papillomavirus (HPV) is the causative agent for cervical cancer. The HPV E7 oncogene promotes S-phase entry from quiescent state in the presence of elevated cell cycle inhibitor p27Kip1, a function that may contribute to carcinogenesis. However, the mechanism by which HPV E7 induces quiescent cells to entry into S-phase is not fully understood. Interestingly, we found that Dyrk1B, a dual-specificity kinase and negative regulator of cell proliferation in quiescent cells, was upregulated in E7 expressing cells. Surprisingly and in contrast to what was previously reported, Dyrk1B played a positive role in S-phase entry of quiescent HPV E7 expressing cells. Mechanistically, Dyrk1B contributed to p27 phosphorylation (at serine 10 and threonine 198), which was important for the proliferation of HPV E7 expressing cells. Moreover, Dyrk1B up-regulated HPV E7. Taken together, our studies uncovered a novel function of Dyrk1B in high-risk HPV E7-mediated cell proliferation. Dyrk1B may serve as a target for therapy in HPV-associated cancers.
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    • "HPV16 E6 and E7 proteins could also activate Akt/mTORC1 signaling and boost cell survival (Menges et al. 2006, Spangle and Munger 2010). HPV16 E7 forces primary keratinocytes to re-replicate PV DNA by inducing overexpression of Cdt1 (Fan et al. 2013 ); additionally , E7 activity correlates with increased expression of MCMs and PCNA as well as increased replication (Xue et al. 2010 ). HPV16 E6 induces MCM7 ubiquitination in an E6-AP-dependent manner, though the significance of this event is unclear (Kuhne and Banks 1998). "
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