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Etude structurale et fonctionnelle du complexe ZEBRA / ADN méthylé

Abstract : Epstein-Barr virus is a γ-herpesvirus that infects over 95% of the world population. The viral transcription factor ZEBRA is responsible for switching infection from the latent to the lytic phase. ZEBRA, a member of the (bZIP) protein family, activates the promoters of lytic EBV genes by recognizing specific DNA sites called ZEBRA-responsive elements (ZREs). ZEBRA binds preferentially to certain ZREs when these are methylated on CpG motifs, including a key target site (ZRE2) within the promoter of the immediate-early gene BRLF1. This activity is unique to ZEBRA among known transcription factors and is critical for lytic cycle activation, as the EBV genome is highly methylated during latency. We determined the crystal structure of ZEBRA's DNA-binding domain in complex with a methylated ZRE2 site. Structural analysis combined with mutagenesis and binding studies suggest a detailed mechanism by which ZEBRA preferentially recognizes methylated DNA. In parallel, we developed a high throughput assay to identify small molecules that inhibit ZEBRA's DNA-binding activity. This work substantially advances our understanding of ZEBRA-mediated lytic cycle activation and will potentially aid in the development of new therapeutic agents against EBV-associated disease.
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https://tel.archives-ouvertes.fr/tel-00356802
Contributor : Priscilla Pagniez <>
Submitted on : Wednesday, January 28, 2009 - 4:44:15 PM
Last modification on : Saturday, June 6, 2020 - 2:35:23 PM
Long-term archiving on: : Tuesday, June 8, 2010 - 9:33:20 PM

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  • HAL Id : tel-00356802, version 1
  • PRODINRA : 250005

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CNRS | INRA | UJF | I2BC | INRAE

Citation

Priscilla Pagniez. Etude structurale et fonctionnelle du complexe ZEBRA / ADN méthylé. Biochimie [q-bio.BM]. Université Joseph-Fourier - Grenoble I, 2008. Français. ⟨tel-00356802⟩

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