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

Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324 USA.
Journal of Virology (Impact Factor: 4.44). 11/2012; 87(2). DOI: 10.1128/JVI.02038-12
Source: PubMed


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 re-replication, a process of successive rounds of host DNA replication without entering mitosis. Interestingly, the DNA replication initiation factor Cdt1, whose uncontrolled expression induces re-replication in human cancer cells, is up-regulated in E7 expressing cells. Moreover, down-regulation of Cdt1 impaires the ability of E7 to induce re-replication. These results demonstrate an important role for Cdt1 in HPV E7-induced re-replication and shed light on mechanisms by which HPV induces genomic instability.

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    • "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]. "
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