Abstract
Epstein–Barr virus (EBV) immortalizes human B-lymphocytes and is implicated in the pathogenesis of lymphoid and epithelial cell malignancies. The EBV nuclear antigen (EBNA)-1 induces the accumulation of reactive oxygen species (ROS), which enables B-cell immortalization but causes oxidative DNA damage and triggers antiproliferative DNA damage responses. By comparing pairs of EBV-negative and -positive tumor cell lines we found that, while associated with the accumulation of oxidized nucleotides, EBV carriage promotes the concomitant activation of oxo-dNTP sanitization and purging pathways, including upregulation of the nucleoside triphosphatase mut-T homolog 1 (MTH1) and the DNA glycosylases 8-oxoguanine-glycosylase-1 (OGG1) and mut-Y homolog (MUTYH). Expression of EBNA1 was reversibly associated with transcriptional activation of this cellular response. DNA damage and apoptosis were preferentially induced in EBNA1-positive cell lines by treatment with MTH1 inhibitors, suggesting that virus carriage is linked to enhanced vulnerability to oxidative stress. MTH1, OGG1, and MUTYH were upregulated upon EBV infection in primary B-cells and treatment with MTH1 inhibitors prevented B-cell immortalization. These findings highlight an important role of the cellular antioxidant response in sustaining EBV infection, and suggests that targeting this cellular defense may offer a novel approach to antiviral therapy and could reduce the burden of EBV associated cancer.
Highlights
Chronic infections by DNA tumor viruses, including oncogenic papilloma (HPV) and polyoma (HPyV) viruses, hepatitis B virus (HBV) and the herpesviruses Epstein–Barr virus (EBV) and Kaposi sarcoma virus (KSHV), account for approximately ten percent of all human malignancies worldwide [1]
It has been argued that the reliance on these protective mechanisms may render malignant cells vulnerable to therapeutic interventions that alter the cellular redox balance or target the repair of oxidated DNA [20]. In this investigation we have explored the mechanisms by which EBV infected cells overcome the antiproliferative effects of the elevated levels of reactive oxygen species (ROS) induced by EBV nuclear antingen-1 (EBNA1)
By comparing pairs of EBV-negative and -positive cell lines derived from lymphoid and epithelial cell malignancies, we found that EBV carriage is consistently associated with upregulation of the nucleoside triphosphatase mut-T homolog 1 (MTH1) that sanitizes oxidized purines from the free nucleotide pool, and components of the BER and NER pathways, including the glycosylases 8-Oxoguanine glycosylase (OGG1) and mut-Y homolog (MUTYH) that purge oxidized bases from DNA
Summary
Chronic infections by DNA tumor viruses, including oncogenic papilloma (HPV) and polyoma (HPyV) viruses, hepatitis B virus (HBV) and the herpesviruses Epstein–Barr virus (EBV) and Kaposi sarcoma virus (KSHV), account for approximately ten percent of all human malignancies worldwide [1]. It has been argued that the reliance on these protective mechanisms may render malignant cells vulnerable to therapeutic interventions that alter the cellular redox balance or target the repair of oxidated DNA [20] In this investigation we have explored the mechanisms by which EBV infected cells overcome the antiproliferative effects of the elevated levels of ROS induced by EBNA1. Treatment with the MTH1 inhibitors TH588 and (S)-Crizotinib selectively induced DNA damage and apoptosis in EBV-positive cell lines and prevented the establishment of EBV transformed lymphoblastoid cell lines from freshly infected B-lymphocytes, suggesting that activation of the cellular defense against oxidative stress plays a central role in promoting the growth transformation and survival of EBV infected cells
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