Activation of the host gene egr1 is essential for the lytic replication of Epstein–Barr virus (EBV). egr1 is activated by Zta (BZLF1, ZEBRA). Zta interacts directly with DNA through a series of closely related Zta-response elements (ZREs). Here we dissect the mechanism used by Zta to interact with the egr1 promoter and identify a weak interaction with egr1ZRE that is dependent on the distal part of egr1ZRE. Furthermore, we demonstrate that the ability of Zta to interact with egr1ZRE is enhanced at least tenfold by methylation. The ability of Zta to transactivate a reporter construct driven by the egr1 promoter can be enhanced by methylation. As the ability of Zta to interact with a methylated ZRE in the EBV genome correlates with its ability to activate the expression of the endogenous viral gene BRLF1, this suggests that Zta may also have the capability to overturn epigenetic control of egr1.
BhendeP. M.,
SeamanW. T.,
DelecluseH. J.,
KenneyS. C.2005; BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. J Virol 79:7338–7348[CrossRef]
ChagantiS.,
MaC. S.,
BellA. I.,
Croom-CarterD.,
HislopA. D.,
TangyeS. G.,
RickinsonA. B.2008; Epstein–Barr virus persistence in the absence of conventional memory B cells: IgM+IgD+CD27+ B cells harbor the virus in X-linked lymphoproliferative disease patients. Blood 112:672–679[CrossRef]
ConacherM.,
CallardR.,
McAulayK.,
ChapelH.,
WebsterD.,
KumararatneD.,
ChandraA.,
SpickettG.,
HopwoodP. A.,
CrawfordD. H.2005; Epstein-Barr virus can establish infection in the absence of a classical memory B-cell population. J Virol 79:11128–11134[CrossRef]
FalzonM.,
KuffE. L.1991; Binding of the transcription factor EBP-80 mediates the methylation response of an intracisternal A-particle long terminal repeat promoter. Mol Cell Biol 11:117–125
FeederleR.,
KostM.,
BaumannM.,
JanzA.,
DrouetE.,
HammerschmidtW.,
DelecluseH. J.2000; The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J 19:3080–3089[CrossRef]
GutschD. E.,
Holley-GuthrieE. A.,
ZhangQ.,
SteinB.,
BlanarM. A.,
BaldwinA. S.,
KenneyS. C.1994; The bZIP transactivator of Epstein-Barr virus, BZLF1, functionally and physically interacts with the p65 subunit of NF- κ B. Mol Cell Biol 14:1939–1948
HestonL.,
El-GuindyA.,
CountrymanJ.,
Dela CruzC.,
DelecluseH. J.,
MillerG.2006; Amino acids in the basic domain of Epstein-Barr virus ZEBRA protein play distinct roles in DNA binding, activation of early lytic gene expression, and promotion of viral DNA replication. J Virol 80:9115–9133[CrossRef]
HicksM. R.,
Al-MehairiS. S.,
SinclairA. J.2003; The zipper region of Epstein-Barr virus bZIP transcription factor Zta is necessary but not sufficient to direct DNA binding. J Virol 77:8173–8177[CrossRef]
HollerM.,
WestinG.,
JiricnyJ.,
SchaffnerW.1988; Sp1 transcription factor binds DNA and activates transcription even when the binding site is CpG methylated. Genes Dev 2:1127–1135[CrossRef]
Iguchi-ArigaS. M.,
SchaffnerW.1989; CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. Genes Dev 3:612–619[CrossRef]
KarlssonQ. H.,
SchelcherC.,
VerrallE.,
PetosaC.,
SinclairA. J.2008a; Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. PLoS Pathog 4:e1000005[CrossRef]
KarlssonQ. H.,
SchelcherC.,
VerrallE.,
PetosaC.,
SinclairA. J.2008b; The reversal of epigenetic silencing of the EBV genome is regulated by viral bZIP protein. Biochem Soc Trans 36:637–639[CrossRef]
KouzaridesT.,
PackhamG.,
CookA.,
FarrellP. J.1991; The BZLF1 protein of EBV has a coiled coil dimerization domain without a heptad leucine repeat but with homology to the C/EBP leucine zipper. Oncogene 6:195–204
ManciniD. N.,
RodenhiserD. I.,
AinsworthP. J.,
O'MalleyF. P.,
SinghS. M.,
XingW.,
ArcherT. K.1998; CpG methylation within the 5′ regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site. Oncogene 16:1161–1169[CrossRef]
SchelcherC.,
ValenciaS.,
DelecluseH. J.,
HicksM.,
SinclairA. J.2005; Mutation of a single amino acid residue in the basic region of the Epstein-Barr virus (EBV) lytic cycle switch protein Zta (BZLF1) prevents reactivation of EBV from latency. J Virol 79:13822–13828[CrossRef]
SeyfertV. L.,
McMahonS.,
GlennW.,
CaoX. M.,
SukhatmeV. P.,
MonroeJ. G.1990; Egr-1 expression in surface Ig-mediated B cell activation. Kinetics and association with protein kinase C activation. J Immunol 145:3647–3653
SistaN. D.,
PaganoJ. S.,
LiaoW.,
KenneyS.1993; Retinoic acid is a negative regulator of the Epstein-Barr virus protein (BZLF1) that mediates disruption of latent infection. Proc Natl Acad Sci U S A 90:3894–3898[CrossRef]
SistaN. D.,
BarryC.,
SampsonK.,
PaganoJ.1995; Physical and functional interaction of the Epstein-Barr virus BZLF1 transactivator with the retinoic acid receptors RAR α and RXR α . Nucleic Acids Res 23:1729–1736[CrossRef]
SpeckS. H.,
ChatilaT.,
FlemingtonE.1997; Reactivation of Epstein-Barr virus: regulation and function of the BZLF1 gene. Trends Microbiol 5:399–405[CrossRef]
SukhatmeV. P.,
CaoX. M.,
ChangL. C.,
Tsai-MorrisC. H.,
StamenkovichD.,
FerreiraP. C.,
CohenD. R.,
EdwardsS. A.,
ShowsT. B.other authors1988; A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell 53:37–43[CrossRef]
TierneyR. J.,
KirbyH. E.,
NagraJ. K.,
DesmondJ.,
BellA. I.,
RickinsonA. B.2000; Methylation of transcription factor binding sites in the Epstein-Barr virus latent cycle promoter Wp coincides with promoter down-regulation during virus-induced B-cell transformation. J Virol 74:10468–10479[CrossRef]
WangP.,
DayL.,
DheekolluJ.,
LiebermanP. M.2005; A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. J Virol 79:13298–13309[CrossRef]
WuF. Y.,
ChenH.,
WangS. E.,
ApRhysC. M.,
LiaoG.,
FujimuroM.,
FarrellC. J.,
HuangJ.,
HaywardS. D.,
HaywardG. S.2003; CCAAT/enhancer binding protein α interacts with ZTA and mediates ZTA-induced p21CIP-1 accumulation and G1 cell cycle arrest during the Epstein-Barr virus lytic cycle. J Virol 77:1481–1500[CrossRef]
ZhangQ.,
GutschD.,
KenneyS.1994; Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr virus latency. Mol Cell Biol 14:1929–1938