title: Role of Cdc6 in re-replication in cells expressing human papillomavirus E7 oncogene.
abstract: The E7 oncoprotein of high-risk human papillomavirus (HPV) types induces DNA re-replication that contributes to carcinogenesis; however, the mechanism is not fully understood. To better understand the mechanism by which E7 induces re-replication, we investigated the expression and function of cell division cycle 6 (Cdc6) in E7-expressing cells. Cdc6 is a DNA replication initiation factor and exhibits oncogenic activities when overexpressed. We found that in E7-expressing cells, the steady-state level of Cdc6 protein was upregulated and its half-life was increased. Cdc6 was localized to the nucleus and associated with chromatin, especially upon DNA damage. Importantly, downregulation of Cdc6 reduced E7-induced re-replication. Interestingly, the level of Cdc6 phosphorylation at serine 54 (S54P) was increased in E7-expressing cells. S54P was associated with an increase in the total amount of Cdc6 and chromatin-bound Cdc6. DNA damage-enhanced upregulation and chromatin binding of Cdc6 appeared to be due to downregulation of cyclin-dependent kinase 1 (Cdk1) as Cdk1 knockdown increased Cdc6 levels. Furthermore, Cdk1 knockdown or inhibition led to re-replication. These findings shed light on the mechanism by which HPV induces genomic instability and may help identify potential targets for drug development.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01532, USA, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xian 710032, China and.
authors.forename: Xueli
authors.initials: X
authors.lastname: Fan
authors.affiliation: The Cancer Research Center, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yunying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01532, USA, The Cancer Research Center, Shandong University School of Medicine, Jinan, Shandong 250012, China jxchen@sdu.edu.cn.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D016203:CDC2 Protein Kinase; D063646:Carcinogenesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D055786:Gene Knockout Techniques; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000473:pathology / Q000821:virology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics / Q000472:pathogenicity; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D061251:Primary Cell Culture
chemical_list: C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases