Abstract
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.
Highlights
Two earlier studies reported contradictory findings on the ability of chloroquine to lyticallyactivate Epstein-Barr virus (EBV) in human B lymphocytes [1,2]
We show that repression of EBV replication is disrupted by the antimalarial drug chloroquine which modifies an otherwise normal cellular mechanism that repairs DNA, to influence gene expression through a process known as chromatin remodeling
This finding a) reveals a new connection between the DNA repair machinery and gene regulation and b) resolves a long-standing dispute over whether chloroquine increases EBV replication, thereby contributing to endemic Burkitt lymphoma, a cancer almost uniformly associated with EBV
Summary
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. 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. A key feature of herpesviruses is the ability to restrict the number of latently/quiescently infected cells that respond to lytic triggers by producing infectious virions. For KSHV, STAT3 functions via the universal transcriptional co-repressor Kruppel-associated Box (KRAB)-associated protein (KAP)-1 [7]–prompting us to investigate the contribution of KAP1/tripartite motif protein 28 (TRIM28) towards lytic susceptibility of EBV
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