Research Article: Chloroquine triggers Epstein-Barr virus replication through phosphorylation of KAP1/TRIM28 in Burkitt lymphoma cells

Date Published: March 1, 2017

Publisher: Public Library of Science

Author(s): Xiaofan Li, Eric M. Burton, Sumita Bhaduri-McIntosh, Paul M. Lieberman.


Trials to reintroduce chloroquine into regions of Africa where P. falciparum has regained susceptibility to chloroquine are underway. However, there are long-standing concerns about whether chloroquine increases lytic-replication of Epstein-Barr virus (EBV), thereby contributing to the development of endemic Burkitt lymphoma. We report that chloroquine indeed drives EBV replication by linking the DNA repair machinery to chromatin remodeling-mediated transcriptional repression. Specifically, chloroquine utilizes ataxia telangiectasia mutated (ATM) to phosphorylate the universal transcriptional corepressor Krüppel-associated Box-associated protein 1/tripartite motif-containing protein 28 (KAP1/TRIM28) at serine 824 –a mechanism that typically facilitates repair of double-strand breaks in heterochromatin, to instead activate EBV. Notably, activation of ATM occurs in the absence of detectable DNA damage. These findings i) clarify chloroquine’s effect on EBV replication, ii) should energize field investigations into the connection between chloroquine and endemic Burkitt lymphoma and iii) provide a unique context in which ATM modifies KAP1 to regulate persistence of a herpesvirus in humans.

Partial Text

Two earlier studies reported contradictory findings on the ability of chloroquine to lytically (re)activate Epstein-Barr virus (EBV) in human B lymphocytes [1,2]. This left open the debate on whether chloroquine might contribute to the high rates of endemic Burkitt lymphoma (eBL) in malaria holoendemic areas of Africa. eBL is almost uniformly associated with EBV and is thought to arise from germinal center B cells harboring clonal EBV in every cell of the tumor [3]. While we did not set out to address the possibility of a link between chloroquine and EBV lytic replication, our investigations into the property of partial permissiveness of EBV [4,5], a member of the herpesvirus family and a WHO group I carcinogen, reveal that chloroquine activates EBV lytic cycle in eBLs.

Our work demonstrates that EBV has appropriated components of the DNA repair machinery typically operational at heterochromatin DNA to regulate the balance between lytic (re)activation and persistence. While ATM has previously been shown to be required for efficient EBV lytic activation [18–20], the precise mechanism and the substrate for its kinase activity were not known. We also demonstrate that endogenous ATM and KAP1 interact in situ resulting in phosphorylation of KAP1. Notably, the signal that activates ATM during EBV lytic cycle does not require DNA double-strand breaks. Furthermore, DNA damage-mediated ATM activation does not necessarily induce EBV replication; either additional triggers are needed to activate transcription of viral genes or damage to viral DNA cripples lytic replication.




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