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Three Epstein–Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints

Oncogene volume 28, pages 3997–4008 (2009)Cite this article

Abstract

Epstein–Barr virus (EBV) has been implicated in the pathogenesis of human malignancies, but its contribution to tumorigenesis is not well understood. EBV carriage is associated with increased genomic instability in Burkitt's lymphoma, suggesting that viral products may induce this tumor phenotype. Using a panel of transfected sublines of the B-lymphoma line BJAB expressing the viral genes associated with latent infection, we show that the EBV nuclear antigens, EBNA-1 and EBNA-3C, and the latent membrane protein 1, LMP-1, independently promote genomic instability, as detected by nonclonal chromosomal aberrations, DNA breaks and phosphorylation of histone H2AX. EBNA-1 promotes the generation of DNA damage by inducing reactive oxygen species (ROS), whereas DNA repair is inhibited in LMP-1-expressing cells through downregulation of the DNA damage-sensing kinase, ataxia telangiectasia mutated (ATM), reduction of phosphorylation of its downstream targets Chk2 and inactivation of the G2 checkpoint. EBNA-3C enhances the propagation of damaged DNA through inactivation of the mitotic spindle checkpoint and transcriptional downregulation of BubR1. Thus, multiple cellular functions involved in the maintenance of genome integrity seem to be independently targeted by EBV, pointing to the induction of genomic instability as a critical event in viral oncogenesis.

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Acknowledgements

We thank L Rymo, M Rowe and J Middledorp for the kind gift of transfected cell lines and antibodies and also many colleagues for helpful discussions. This study was supported by grants awarded by the Swedish Cancer Society, the Swedish Medical Research Council and Karolinska Institutet, Stockholm, Sweden and by the European Community Integrated Project on Infection and Cancer, INCA, Project No. LSHC-CT-2005-018704.

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  1. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

    B Gruhne, R Sompallae & M G Masucci

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  1. B Gruhne
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Correspondence to M G Masucci.

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Gruhne, B., Sompallae, R. & Masucci, M. Three Epstein–Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints. Oncogene 28, 3997–4008 (2009). https://doi.org/10.1038/onc.2009.258

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