An ATM/Chk2-Mediated DNA Damage-Responsive Signaling Pathway Suppresses Epstein-Barr Virus Transformation of Primary Human B Cells

Abstract

SUMMARY Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication nor did the DDR marks co-localize with latent episomes. Rather, a transient period of EBV-induced hyper-proliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoproteins EBNA3C was required to attenuate the EBV-induced DNA damage response We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR which is attenuated by viral latency products to induce cell immortalization.

Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16 INK4A and p14 ARF expression

“…EBNA2 is expressed first and strongly up-regulates MYC (48-50). MYC induces cyclin D2, and cyclin D2-enforced cell cycle entry likely induces CDKN2A p16 and p14 expression (48)(49)(50)(51)(52). CDKN2A p16 INK4A and p14 ARF are partially regulated by different promoters and have different first exons (exon 1α for p16 INK4A and 1β for p14 ARF ), but share exons 2 and 3 (53,54).…”

“…Certainly, constitutive EBNA2-mediated c-myc up-regulation has a central role in EBV-mediated LCL growth (49,62) and almost certainly underlies p16 INK4A and p14 ARF induction in EBV-infected B cells in the absence of EBNA3C or EBNA3A. Forced MYC expression induces p16 INK4A and p14 ARF in normal human diploid fibroblasts and megakaryocytes (42,63).…”

RNAs in Epstein–Barr virions control early steps of infection

“…It has recently been described that, in newly infected cells, before establishment of latency, EBV expresses a small set of viral genes that had previously been classified as immediate-early or early genes of the lytic cycle. At this prelatent stage of infection, the immediate expression of these genes activates resting B cells (8) while protecting them from immediate activation-induced apoptosis (9) and other endogenous stress response signals (10). The prelatent phase is followed by a stable latent phase, characterized by the expression of viral latent genes that support cellular proliferation and sustain the outgrowth of lymphoblastoid cells lines in vitro (11).…”

Exposure to UV radiation and risk of Hodgkin lymphoma: a pooled analysis

“…35 UVR appears to induce regulatory T cells through antigen presentation by UVR-damaged Langerhans cells in the lymph nodes 36 leading to an immunosuppressed state that may be protective, as suggested by the inverse association observed between the use of aspirin and HL risk. [37][38][39] Second, the cellular DNA damage response activated by viral oncogenes such as those associated with EBV 40 could cause tumor suppression by effector T cells when enhanced by UVR exposure, 41 which is known to induce multiple defense mechanisms to counterbalance its potential mutagenic and cytotoxic effects. 42 The DNA damage response acts as an innate barrier to tumorigenesis, 43 whereas a disordered response may lead to lymphomas, including EBV-associated lymphoma.…”