Abstract
The Epstein–Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways. The consequences of DDR inactivation lead to genomic instability and promote cellular transformation. This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation.
Highlights
The Epstein–Barr virus (EBV), a type of human herpesvirus, is classified as a Group 1 carcinogenic agent by the International Agency for Research on Cancer (IARC)
We have summarized the recent findings on the involvement of major DNA damage response (DDR)
Given the DDR functions a transducers in the life cycle
Summary
The Epstein–Barr virus (EBV), a type of human herpesvirus, is classified as a Group 1 carcinogenic agent by the International Agency for Research on Cancer (IARC). During lytic and latent infection of EBV, different sets of viral genes are expressed. Upon the completion of viral DNA replication, the late viral genes are expressed to mediate the processes from capsid assembly to viral DNA packaging, and eventually the release of the virus from infected host cells. Recent studies showed that both latent and lytic viral proteins are implicated during the host DNA damage response, and may contribute to cell transformation and sensitivity of infected cells to DNA damaging agents [25,26,27,28]. We will focus our discussion on how EBV manipulates the DDR signaling pathways during lytic infection to complete the viral DNA replication. Cellular proteins in the family of phosphoinositide-3-kinase-related protein (PIKKs) are involved in mediating the signaling events at sites of DNA damage; these include the ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), which were shown to have close interplay with EBV infection
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