title: Human papillomavirus E7 induces rereplication in response to DNA damage.
abstract: 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 G(2) checkpoint. Upon DNA damage, HPV-16 E7-expressing cells arrest at the G(2) 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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Xueli
authors.initials: X
authors.lastname: Fan
authors.forename: Yingwang
authors.initials: Y
authors.lastname: Liu
authors.forename: Susan A
authors.initials: SA
authors.lastname: Heilman
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002478:Cells, Cultured; D004249:DNA Damage; D004261:DNA Replication; D005260:Female; D015870:Gene Expression; D042822:Genomic Instability; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D011123:Polyploidy; D015854:Up-Regulation
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16