The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species.
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.
Gruhne
Bettina
B
Department of Cell and Molecular Biology, Karolinska Institutet, S-17177 Stockholm, Sweden.
Sompallae
Ramakrishna
R
Marescotti
Diego
D
Kamranvar
Siamak Akbari
SA
Gastaldello
Stefano
S
Masucci
Maria G
MG
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
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