Epstein–Barr virus can inhibit genotoxin-induced G1 arrest downstream of p53 by preventing the inactivation of CDK2

Abstract

Epstein-Barr virus (EBV) is involved in the pathogenesis of several B cell lymphoproliferations, but the precise contribution it makes to the aetiology of each remains unclear. In vitro, the virus has potent growth transforming activity and efficiently induces the continuous proliferation of normal human B cells. A comparison of EBVinfected primary B cells with an isogenic population induced to proliferate by CD40-ligand (CD40L) and IL4 has revealed that EBV can override -by a novel mechanism -the p53/pRb-mediated G1 checkpoint activated in normal B cells by a genotoxic stress. In cells responding to cisplatin, although p53 is stabilized and activated, EBV latent gene expression appears to inhibit the accumulation of newly synthesized p21 WAF1/CIP1 and the downregulation of cyclin D2 that occur in the normal cells. Consequently, in the EBV-infected cells, CDK2 remains active, hyperphosphorylation of pRb is maintained and the replication of damaged DNA can occur. Under conditions of severe genomic stress, this absence of p21 WAF1/CIP1 function can result in apoptosis; however, when damage is less sustained, genomic instability may arise and this in turn could contribute to the development of a variety of EBV-associated B cell malignancies.

Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells

“…EBVpositive BL41/B95.8 cells also accumulated with apparently normal nuclei and 4N DNA content. This indicated that EBV is unable to overcome the G 2 /M arrest after irradiation and is consistent with the results from previous experiments using EBV-immortalized LCLs (5,21).…”

“…Although the tumor suppressor p53 is one of the major targets of oncogenic viruses, several studies have shown that EBV does not specifically target p53 during the transformation of normal B cells into LCLs (1, 2). Nevertheless, recent studies demonstrated that although not able to directly target p53, EBV may still interfere with cell cycle checkpoints at both G 1 /S and G 2 /M phases (15,21,31).…”

“…Following genotoxic stress induced by cisplatin, EBV suppresses a checkpoint downstream of p53 by preventing the inactivation of cdk2 by p21 WAF1/CIP1 , and this appears to involve the modulation of p21 WAF1/CIP1 stability (21). In addition to deregulating a G 1 checkpoint, EBV has been shown to interfere with checkpoints acting at the G 2 /M transition.…”

“…Although the tumor suppressor p53 is one of the major targets of oncogenic viruses, several studies have shown that EBV does not specifically target p53 during the transformation of normal B cells into LCLs (1, 2). Nevertheless, recent studies demonstrated that although not able to directly target p53, EBV may still interfere with cell cycle checkpoints at both G 1 /S and G 2 /M phases (15,21,31).Following genotoxic stress induced by cisplatin, EBV suppresses a checkpoint downstream of p53 by preventing the inactivation of cdk2 by p21 WAF1/CIP1 , and this appears to involve the modulation of p21 WAF1/CIP1 stability (21). In addition to deregulating a G 1 checkpoint, EBV has been shown to interfere with checkpoints acting at the G 2 /M transition.…”

Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma

“…Both transmissible (Bernheim et al, 1981;Klein, 1986) and unstable chromosomal aberrations (Stollmann et al, 1985;Zattara-Cannoni et al, 1996;Chan et al, 2001) are present in EBV-associated malignancies, but the contribution of the virus to this phenotype is not understood. It was suggested that EBV might prime genomic instability by activating specific recombinases (Kuhn-Hallek et al, 1995) by integration (Jox et al, 1997) or by induction of oxidative stress (Gualandi et al, 2001), whereas latent viral genes such as LMP1 and LMP2 could contribute by modulating telomere function and DNA repair Liu et al, 2005), or by enhancing the sensitivity to DNAdamaging agents (O'Nions and Allday, 2003;Liu et al, 2004). However, there is no conclusive evidence for the mutagenic potential of the virus.…”