Epstein-Barr Virus (EBV)-Related Lymphoproliferative Disorders in Ataxia Telangiectasia: Does ATM Regulate EBV Life Cycle?

Abstract

Epstein-Barr virus (EBV) is an ubiquitous herpesvirus with a tropism for epithelial cells (where lytic replication occurs) and B-cells (where latency is maintained). EBV persists throughout life and chronic infection is asymptomatic in most individuals. However, immunocompromised patients may be unable to control EBV infection and are at increased risk of EBV-related malignancies, such as diffuse large B-cell lymphomas or Hodgkin's lymphomas. Ataxia telangiectasia (AT) is a primary immunodeficiency caused by mutations in the ATM gene and associated with an increased incidence of cancers, particularly EBV-associated lymphomas. However, the immune deficiency present in AT patients is often too modest to explain the increased incidence of EBV-related malignancies. The ATM defect in these patients could therefore impair the normal regulation of EBV latency in B-cells, thus promoting lymphomagenesis. This suggests that ATM plays a role in the normal regulation of EBV latency. ATM is a serine/threonine kinase involved in multiple cell functions such as DNA damage repair, cell cycle regulation, oxidative stress, and gene expression. ATM is implicated in the lytic cycle of EBV, where EBV uses the activation of DNA damage repair pathway to promote its own replication. ATM regulates the latent cycle of the EBV-related herpesvirus KSHV and MHV68. However, the contribution of ATM in the control of the latent cycle of EBV is not yet known. A better understanding of the regulation of EBV latency could be harnessed in the conception of novel therapeutic strategies in AT and more generally in all ATM deficient EBV-related malignancies.

Keywords: B-cell; Epstein Barr virus; ataxia telangiectasia; hodgkin lymphoma; latency; lymphomagenesis; non-hodgkin lymphoma; primary immune deficiency.

Figures

Figure 1

ATM activation and downstream signaling in response to DSB. DSB induces a rapid activation of the ATM dimer and the MRN complex, which in turn induces the autophosphorylation and monomerization of ATM protein. ATM becomes fully active and phosphorylates a large subset of downstream proteins including γH2AX which serves as a scaffold for the recruitment of repair proteins, MDC1, BP53, and BRCA1 involved in DNA repair, CHK2 involved in cell cycle arrest and p53 involved apoptosis induction. CHK2 also phosphorylates P53 to promote cell-cycle arrest or apoptosis.

Figure 2

Role Of Atm In Ebv Life Cycle Regulation (A) The central role of ATM in the replication compartment of EBV. In the lytic cycle, DNA damage response proteins such as γH2AX, the MRN complex, ATM, SP1, RPA, RAD51, and RAD52 bind the viral genome and promote replication of the virus. Viral proteins are shown in red. BGLF4 phosphorylates H2AX, ATM, and TIP60 which acetylate ATM to promote this replication. ATM phosphorylates and activates Sp1 which is necessary to the formation of the replication compartment comprising a large complex of six core viral replication proteins (BSLF1, BALF2, BBLF2/3, BALF5, BMRF1, and BBLF4). ATM phosphorylates and activates P53, which is inhibited and driven by BZLF1 to the replication compartment. BZLF1 is a major transactivator of the lytic genes promoter OryLyt. P53 binds to Sp1 and promote the activation of OryLyt. P53 is regulated by proteasomal degradation and can induce apoptosis, but BHRF1 inhibits a panel of pro-apoptotic proteins. (B) ATM is regulated by EBV during latency. In the latent cycle, LMP1 downregulates ATM, and upregulates Bmi-1 which also downregulates ATM. On the other hand, LMP1 activates the NFκB pathway which activates ATM. EBNA-1 upregulates NOX2, which generates reactive oxygen species (ROS) that could activate ATM. Once activated, ATM activates CHK2 which promotes cell cycle arrest. However, EBNA-3C and EBNA-3A inhibit many proteins involved in cell cycle control. (C) Potential involvement of ATM in the regulation of EBV latency. ATM could be involv ed in inhibiting the expression of certain viral oncogenes, such as the main viral oncogene LMP1. ATM could also favor the progressive restriction of EBV latency, from type III latency to type I. In type III latency, EBNA-2 interacts with the target of the Notch pathway RBP-JK, recruits coactivators and induces the transcription of pro-proliferative genes like Myc. In type II latency, EBNA-3 replaces EBNA-2, and recruits co-repressors, thus preventing prolonged expression of MYC. In type I latency, RBP-JK is associated with corepressors and only EBNA-1 remains expressed, which allows the attachment of EBV episome on cellular chromosomes.