title: Epstein-Barr virus DNase (BGLF5) induces genomic instability in human epithelial cells.
abstract: Epstein-Barr Virus (EBV) DNase (BGLF5) is an alkaline nuclease and has been suggested to be important in the viral life cycle. However, its effect on host cells remains unknown. Serological and histopathological studies implied that EBV DNase seems to be correlated with carcinogenesis. Therefore, we investigate the effect of EBV DNase on epithelial cells. Here, we report that expression of EBV DNase induces increased formation of micronucleus, an indicator of genomic instability, in human epithelial cells. We also demonstrate, using gammaH2AX formation and comet assay, that EBV DNase induces DNA damage. Furthermore, using host cell reactivation assay, we find that EBV DNase expression repressed damaged DNA repair in various epithelial cells. Western blot and quantitative PCR analyses reveal that expression of repair-related genes is reduced significantly in cells expressing EBV DNase. Host shut-off mutants eliminate shut-off expression of repair genes and repress damaged DNA repair, suggesting that shut-off function of BGLF5 contributes to repression of DNA repair. In addition, EBV DNase caused chromosomal aberrations and increased the microsatellite instability (MSI) and frequency of genetic mutation in human epithelial cells. Together, we propose that EBV DNase induces genomic instability in epithelial cells, which may be through induction of DNA damage and also repression of DNA repair, subsequently increases MSI and genetic mutations, and may contribute consequently to the carcinogenesis of human epithelial cells.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chung-Chun
authors.initials: CC
authors.lastname: Wu
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Liu
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chang
authors.forename: Chih-Yeu
authors.initials: CY
authors.lastname: Fang
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Chou
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Liao
authors.forename: Kuan-Lin
authors.initials: KL
authors.lastname: Kuo
authors.forename: Shih-Lung
authors.initials: SL
authors.lastname: Hsu
authors.forename: Yi-Ren
authors.initials: YR
authors.lastname: Chen
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.forename: Yu-Lian
authors.initials: YL
authors.lastname: Chen
authors.forename: Hsin-Ying
authors.initials: HY
authors.lastname: Chuang
authors.forename: Chia-Huei
authors.initials: CH
authors.lastname: Lee
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Wun-Shaing
authors.initials: WS
authors.lastname: Wayne Chang
authors.forename: Jen-Yang
authors.initials: JY
authors.lastname: Chen
mesh_terms: D002460:Cell Line; D002869:Chromosome Aberrations; D053960:DNA Breaks; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D003851:Deoxyribonucleases / Q000378:metabolism*; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D048629:Micronuclei, Chromosome-Defective; D053842:Microsatellite Instability; D009154:Mutation; D014176:Protein Biosynthesis; D014158:Transcription, Genetic; D014466:Ultraviolet Rays; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; D003851:Deoxyribonucleases; C083203:deoxyribonuclease, Epstein-Barr virus