The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection

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...

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Bibliographic Details
Published in:PLoS pathogens 2021-09, Vol.17 (9), p.e1009954-e1009954
Main Authors: Li, Jinlin, Nagy, Noemi, Liu, Jiangnan, Gupta, Soham, Frisan, Teresa, Hennig, Thomas, Cameron, Donald P, Baranello, Laura, Masucci, Maria G
Format: Article
Language:English
Subjects:
Antibodies
Biology and Life Sciences
Cell survival
Deoxyribonucleic acid
Development and progression
DNA
DNA damage
DNA repair
DNA topoisomerase (ATP-hydrolysing)
DNA topoisomerase II
Enzymes
Epstein-Barr virus
Epstein-Barr virus diseases
Etoposide
Gene expression
Genetic aspects
Infections
Lymphoid cell lines
Medicin och hälsovetenskap
Medicine and health sciences
Phosphodiesterase
Physiological aspects
Poisoning
Proteins
Proteolysis
Research and Analysis Methods
Substrates
Survival
Toxicity
Ubiquitin
Viral proteins
Viruses
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1009954