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


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.

Full-text preview

Available from:
  • Source
    • "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.
    Full-text · Article · Sep 2015 · Radiotherapy and Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: E7 is an accessory protein that is not encoded by all papillomaviruses. The E7 amino terminus contains two regions of similarity to conserved regions 1 and 2 of the adenovirus E1A protein, which are also conserved in the simian vacuolating virus 40 large tumor antigen. The E7 carboxyl terminus consists of a zinc-binding motif, which is related to similar motifs in E6 proteins. E7 proteins play a central role in the human papillomavirus life cycle, reprogramming the cellular environment to be conducive to viral replication. E7 proteins encoded by the cancer-associated alpha human papillomaviruses have potent transforming activities, which together with E6, are necessary but not sufficient to render their host squamous epithelial cell tumorigenic. This article strives to provide a comprehensive summary of the published research studies on human papillomavirus E7 proteins.
    No preview · Article · May 2013 · Virology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cervical cancer remains a great problem for woman health, as it is the second deadly cancer of females worldwide. The infection of human papilloma virus (HPV) is the major risk factor for this cancer, although several other factors are also associated. Oxidative stress or antioxidant deficiency has been frequently identified to be associated with cervical cancer. Defects in the antioxidant enzyme systems are reported to play important role behind this antioxidant deficiency, which is responsible for the production of reactive oxygen species and ultimately, DNA damage in cervical cells. In response, cells become more vulnerable to HPV infection for cervical cancer development. Recently, antioxidant therapies or dietary supplementation of antioxidants have gained considerable interests in the cervical cancer treatment. In this study, we have reviewed the association of defective antioxidant systems and cervical cancer development. The recent advances in both of the basic and clinical research focusing on possible antioxidant therapy have also been discussed.
    No preview · Article · Aug 2013 · Tumor Biology
Show more