title: The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species.
abstract: The Epstein-Barr virus (EBV) nuclear antigen (EBNA)-1 is the only viral protein expressed in all EBV-carrying malignancies, but its contribution to oncogenesis has remained enigmatic. We show that EBNA-1 induces chromosomal aberrations, DNA double-strand breaks, and engagement of the DNA damage response (DDR). These signs of genomic instability are associated with the production of reactive oxygen species (ROS) and are reversed by antioxidants. The catalytic subunit of the leukocyte NADPH oxidase, NOX2/gp91(phox), is transcriptionally activated in EBNA-1-expressing cells, whereas inactivation of the enzyme by chemical inhibitors or RNAi halts ROS production and DDR. These findings highlight a novel function of EBNA-1 and a possible mechanism by which expression of this viral protein could contribute to malignant transformation and tumor progression.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Bettina
authors.initials: B
authors.lastname: Gruhne
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sompallae
authors.forename: Diego
authors.initials: D
authors.lastname: Marescotti
authors.forename: Siamak Akbari
authors.initials: SA
authors.lastname: Kamranvar
authors.forename: Stefano
authors.initials: S
authors.lastname: Gastaldello
authors.forename: Maria G
authors.initials: MG
authors.lastname: Masucci
mesh_terms: D000956:Antigens, Viral / Q000737:chemistry; D000975:Antioxidants; D020134:Catalytic Domain; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D018450:Disease Progression; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009249:NADP / Q000737:chemistry; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology; D017382:Reactive Oxygen Species; D015533:Transcriptional Activation
chemical_list: D000956:Antigens, Viral; D000975:Antioxidants; D019309:Epstein-Barr Virus Nuclear Antigens; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D009249:NADP; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C417029:EBV-encoded nuclear antigen 1