Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV's transforming genes

Abstract

EBV is a paradigm for human tumor viruses because, although it infects most people benignly, it also can cause a variety of cancers. Both in vivo and in vitro, EBV infects B lymphocytes in G0, induces them to become blasts, and can maintain their proliferation in cell culture or in vivo as tumors. How EBV succeeds in these contrasting cellular environments in expressing its genes that control the host has not been explained. We have genetically dissected the EBV nuclear antigen 1 (EBNA1) gene that is required for replication of the viral genome, to elucidate its possible role in the transcription of viral genes. Strikingly, EBNA1 is essential to drive transcription of EBV's transforming genes after infection of primary B lymphocytes.transcriptional regulation ͉ high-mobility group A protein ͉ HMGA1a

The plasmid replicon of Epstein–Barr virus: Mechanistic insights into efficient, licensed, extrachromosomal replication in human cells

“…EBP2 was found to bind LR2 of EBNA1, and LR2 is not required for EBNA1's support of oriP replication (Shire, Ceccarelli et al 1999), (Mackey and Sugden 1999), (Sears, Ujihara et al 2004). Additionally, the Nterminal half of EBNA1 can be replaced with cellular proteins containing AT-hook motifs, such as HMGA1a, and still retain replicative function (Hung, Kang et al 2001), (Sears, Kolman et al 2003) (Altmann, Pich et al 2006). These findings indicate that it likely is the AT-hook activities of LR1 and LR2 and not LR2's binding of EBP2 that are required for the maintenance of oriP in human cells.…”

“…FR is composed of 21 imperfect copies of a 30bp repeat and contains 20 high affinity EBNA1-binding sites (Figure 1). When FR is bound by EBNA1, it both serves as a transcriptional enhancer of promoters in cis up to 10kb away (Reisman and Sugden 1986), (Yates 1988), (Sugden and Warren 1989), (Wysokenski and Yates 1989), (Gahn and Sugden 1995), (Kennedy and Sugden 2003;Altmann, Pich et al 2006), and contributes to the nuclear retention and faithful maintenance of FR-containing plasmids (Langle-Rouault, Patzel et al 1998), (Kirchmaier and Sugden 1995), (Wang, Lindner et al 2006) (Nanbo, Sugden et al submitted). The efficient partitioning of oriP plasmids is also likely attributable to FR.…”

“…The C-terminal half of LR1 is composed of amino acids other than the repeated Arg-Gly of the N-terminal half, and is termed Unique Region 1 (UR1). UR1 is necessary for EBNA1 to activate transcription efficiently from transfected and integrated reporter DNAs containing FR (Wu, Kapoor et al 2002;Kennedy and Sugden 2003;Altmann, Pich et al 2006). UR1 is also essential for the efficient transformation of B-cells infected by EBV.…”

“…UR1 is also essential for the efficient transformation of B-cells infected by EBV. When a derivative of EBNA1 lacking this domain replaces the wild-type protein in the context of the whole virus, these derivative viruses have 0.1% of the transforming ability of the wild-type virus (Altmann, Pich et al 2006). The presence of the UR1 domain in EBNA1 allows a shift from the Wp promoter, which is used immediately after infection, to the Cp promoter 5 days post-infection (Figure 1.A) (ibid).…”

The Viral Etiology of AIDS‐Associated Malignancies

“…EBNA-1 is also a transcriptional regulator that modulates the activity of the viral promoters: Wp and Cp and its own latent promoter Qp. Moreover, EBNA-1 is essential to drive transcription of EBV's transforming genes after infection of primary B lymphocytes (Altmann et al, 2006)…”