title: HPV-16 E6 oncoprotein impairs the fidelity of DNA end-joining via p53-dependent and -independent pathways.
abstract: We previously reported that the E6 oncoprotein of high-risk human papillomavirus (HPV) caused genetic instability and oncogenesis by disrupting cellular DNA repair. Here, to investigate the effect of different domains of E6 on DNA double-strand break (DSB) repair, we infected normal human oral fibroblasts (NHOF) with retroviruses expressing wild-type (wt) or mutant (mt) HPV-16 E6 and examined the cellular DNA end-joining (EJ) activity. The cells expressing E6 showed not only a diminution of error-free DNA EJ but also an increase in erroneous DNA EJ capacity if compared with cells without wt E6. Analysis of DNA EJ activities from the cells expressing mt HPV-16 E6 indicated that binding to p53 and the presence of both intact zinc finger domains of E6 are necessary for inducing the E6-mediated aberrant DNA EJ activity. Also, deletion of the PDZ binding C-terminal region reduced this activity by 50%. These findings suggest that E6 can disrupt the fidelity of DSB repair via both p53-dependent and -independent pathways and the impaired fidelity might contribute to the development of genetic instability found in HPV-associated cancer.
authors.affiliation: UCLA School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Ki-Hyuk
authors.initials: KH
authors.lastname: Shin
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Ahn
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
authors.forename: Philip K
authors.initials: PK
authors.lastname: Lim
authors.forename: Felix K
authors.initials: FK
authors.lastname: Yip
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Baluda
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts; D016158:Genes, p53; D052162:Human papillomavirus 16 / Q000472:pathogenicity*; D006801:Humans; D009369:Neoplasms / Q000503:physiopathology / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D012190:Retroviridae; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53