Journal article
Three Epstein-Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints
Oncogene, Vol.28(45), pp.3997-4008
11/12/2009
DOI: 10.1038/onc.2009.258
PMID: 19718051
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 G(2) 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. Oncogene (2009) 28, 3997-4008; doi:10.1038/onc.2009.258; published online 31 August 2009
Details
- Title: Subtitle
- Three Epstein-Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints
- Creators
- B. Gruhne - Karolinska InstitutetR. Sompallae - Karolinska InstitutetM. G. Masucci - Karolinska Institutet
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.28(45), pp.3997-4008
- Publisher
- Springer Nature
- DOI
- 10.1038/onc.2009.258
- PMID
- 19718051
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Number of pages
- 12
- Grant note
- Swedish Cancer Society Swedish Medical Research Council; Swedish Medical Research Council (SMRC) LSHC-CT-2005-018704 / INCA; Institut National du Cancer (INCA) France Karolinska Institutet, Stockholm, Sweden
- Language
- English
- Date published
- 11/12/2009
- Academic Unit
- Pathology
- Record Identifier
- 9984622754902771
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