Epstein-Barr Virus Hijacks DNA Damage Response Transducers to Orchestrate Its Life Cycle

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.

Keywords: DNA damage response; Epstein–Barr virus; lytic reactivation.

Figure 1

ATM (ataxia telangiectasia mutated)-mediated DDR (DNA damage response) signaling pathway. ATM phosphorylates H2AX/H2A and promotes the recruitment of E3 ubiquitin-protein ligase RNF8 (RNF8) and E3 ubiquitin-protein ligase RNF168 (RNF168) ubiquitin ligase. The RNF8 and RNF168 mediate the polyubiquitination of Histone H2A/ H2AX (H2AX/H2A) and recruit the BRCA1/RAP80/Abraxas for activation of the HR (homologous repair) pathway. The recruitment of TP53-binding protein 1 (53BP1) requires the methylation of the histone H4 Lysine 20. The red arrow indicates the phosphorylation of H1, H2A and H2AX events and the black arrow indicates the progression events take place at DNA breakage sites.

Figure 2

ATR (ATM and Rad3-related) mediates DNA repair during replication fork stalling. ATR kinase activity is stimulated by DNA topoisomerase 2-binding protein 1 (TopBP1) or Ewing tumor-associated antigen 1 (ETAA1). The activated ATR-ATRIP phosphorylates CHK1 through the Claspin/Timeless complex. The red arrow indicates the activation of ATR directly by ETAA1. The black arrow indicates the phosphorylation of Checkpoint kinase 1 (CHK1) through activated ATR.

Figure 3

The recruitment of EBV (Epstein–Barr virus) lytic replication proteins to the oriLyt of the EBV genome. ATM phosphorylates Transcription factor Sp1 (Sp1) at Serine 101 residue. The phosphorylated Sp1 tethers and stabilizes other replication proteins which promote viral DNA replication.

Figure 4

The EBV latent and lytic genes deregulates DDR transducers in EBV-infected cells. A simplified version of signaling pathways is shown here. Viral components (in bold) that activate (red) or suppress (blue) DDR transducers are shown. See texts for detail description. T-bar indicates inhibition effect. The red arrow indicates the activation of proteins. The blue rough arrow shows the increase in STAT3 activation.