Abstract
Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and deubiquitinated TOP2, and stabilized SUMOylated TOP2 trapped in cleavage complexes (TOP2ccs), which halted the DNA damage response to TOP2-induced double strand DNA breaks and promoted cell survival. Induction of the productive virus cycle in epithelial and lymphoid cell lines carrying recombinant EBV encoding the active enzyme was accompanied by TOP2 deubiquitination, accumulation of TOP2ccs and resistance to Etoposide toxicity. The protective effect of BPLF1 was dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair. These findings highlight a previously unrecognized function of BPLF1 in supporting a non-proteolytic pathway for TOP2ccs debulking that favors cell survival and virus production.
Highlights
Epstein–Barr virus (EBV) is a human gamma-herpesvirus that establishes life-long persistent infections in most adults worldwide
We report that the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1 selectively regulates the activity of TOP2 in cells treated with the TOP2 poison Etoposide and during productive infection
We report that TOP2 is a substrate of the deubiquitinating enzymes (DUBs) encoded in the N-terminal domain of the EBV large tegument protein BPLF1 and provide evidence for the capacity of the viral enzyme to promote the non-proteolytic tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent resolution of TOP2 cleavage complexes (TOP2ccs), which enhances cell survival and favors virus production
Summary
Epstein–Barr virus (EBV) is a human gamma-herpesvirus that establishes life-long persistent infections in most adults worldwide. The virus has been implicated in the pathogenesis of a broad spectrum of diseases ranging from infectious mononucleosis (IM) to a variety of lymphoid and epithelial cell malignancies including both Hodgkin and non-Hodgkin lymphomas, undifferentiated nasopharyngeal carcinoma, and gastric cancer [1]. EBV establishes latent or productive infections in different cell types. Few viral genes are expressed resulting in the production of proteins and non-coding RNAs that drive virus persistence and cell proliferation [2]. Productive infection requires the coordinated expression of a large number of immediate early, early and late viral genes, which leads to the assembly of progeny virus and death of the infected cells [3]. Much of the EBV-induced pathology has been attributed to viral latency, the importance of lytic products in the induction of chronic inflammation and malignant transformation is increasingly recognized [4, 5], pointing to inhibition of lytic gene products as a useful strategy for preventing EBV associated diseases
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