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The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species

Gruhne, Bettina, Sompallae, Ramakrishna, Marescotti, Diego, Kamranvar, Siamak Akbari, Gastaldello, Stefano, Masucci, Maria G.
Proceedings of the National Academy of Sciences of the United States of America 2009 v.106 no.7 pp. 2313-2318
DNA damage, Human herpesvirus 4, NAD(P)H oxidase (H2O2-forming), NADP (coenzyme), RNA interference, antigens, antioxidants, carcinogenesis, chemical inhibitors, chromosome aberrations, enzyme inactivation, leukocytes, protein subunits, reactive oxygen species, transcription (genetics)
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/gp91phox, 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.