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Bernaudat, F.* ; Gustems, M. ; Günther, J. ; Oliva, M.F.* ; Buschle, A. ; Göbel,C. ; Pagniez, P.* ; Lupo, J.* ; Signor, L.* ; Müller, C.W.* ; Morand, P.* ; Sattler, M. ; Hammerschmidt, W. ; Petosa, C.*

Structural basis of DNA methylation-dependent site selectivity of the Epstein-Barr virus lytic switch protein ZEBRA/Zta/BZLF1.

Nucleic Acids Res. 50, 490-511 (2021)
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Open Access Gold
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In infected cells, Epstein-Barr virus (EBV) alternates between latency and lytic replication. The viral bZIP transcription factor ZEBRA (Zta, BZLF1) regulates this cycle by binding to two classes of ZEBRA response elements (ZREs): CpG-free motifs resembling the consensus AP-1 site recognized by cellular bZIP proteins and CpG-containing motifs that are selectively bound by ZEBRA upon cytosine methylation. We report structural and mutational analysis of ZEBRA bound to a CpG-methylated ZRE (meZRE) from a viral lytic promoter. ZEBRA recognizes the CpG methylation marks through a ZEBRA-specific serine and a methylcytosine-arginine-guanine triad resembling that found in canonical methyl-CpG binding proteins. ZEBRA preferentially binds the meZRE over the AP-1 site but mutating the ZEBRA-specific serine to alanine inverts this selectivity and abrogates viral replication. Our findings elucidate a DNA methylation-dependent switch in ZEBRA's transactivation function that enables ZEBRA to bind AP-1 sites and promote viral latency early during infection and subsequently, under appropriate conditions, to trigger EBV lytic replication by binding meZREs.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Quellenangaben Volume: 50, Issue: 1, Pages: 490-511 Article Number: , Supplement: ,
Publisher Oxford University Press
Reviewing status Peer reviewed
Grants CNRS
Deutsche Forschungsgemeinschaft
Auvergne-Rhône-Alpes region
Agence Nationale de Recherche