Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Nov 16;9(11):341.
doi: 10.3390/v9110341.

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

Pok Man Hau  1 , Sai Wah Tsao  2
Affiliations
Review

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

Pok Man Hau et al. Viruses. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
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
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
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Epstein A. Why and how epstein-barr virus was discovered 50 years ago. Curr. Top. Microbiol. Immunol. 2015;390:3–15. - PubMed
    1. Young L.S., Yap L.F., Murray P.G. Epstein-barr virus: More than 50 years old and still providing surprises. Nat. Rev. Cancer. 2016;16:789–802. doi: 10.1038/nrc.2016.92. - DOI - PubMed
    1. Chua M.L.K., Wee J.T.S., Hui E.P., Chan A.T.C. Nasopharyngeal carcinoma. Lancet. 2016;387:1012–1024. doi: 10.1016/S0140-6736(15)00055-0. - DOI - PubMed
    1. Tsao S.W., Yip Y.L., Tsang C.M., Pang P.S., Lau V.M., Zhang G., Lo K.W. Etiological factors of nasopharyngeal carcinoma. Oral Oncol. 2014;50:330–338. doi: 10.1016/j.oraloncology.2014.02.006. - DOI - PubMed
    1. Gahn T.A., Schildkraut C.L. The epstein-barr virus origin of plasmid replication, orip, contains both the initiation and termination sites of DNA replication. Cell. 1989;58:527–535. doi: 10.1016/0092-8674(89)90433-9. - DOI - PubMed

MeSH terms

LinkOut - more resources