G-quadruplexes regulate Epstein-Barr virus-encoded nuclear antigen 1 mRNA translation

Pierre Murat, Jie Zhong, Lea Lekieffre, Nathan P. Cowieson, Jennifer L. Clancy, Thomas Preiss, Shankar Balasubramanian, Rajiv Khanna, Judy Tellam*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    200 Citations (Scopus)

    Abstract

    Viruses that establish latent infections have evolved unique mechanisms to avoid host immune recognition. Maintenance proteins of these viruses regulate their synthesis to levels sufficient for maintaining persistent infection but below threshold levels for host immune detection. The mechanisms governing this finely tuned regulation of viral latency are unknown. Here we show that mRNAs encoding gammaherpesviral maintenance proteins contain within their open reading frames clusters of unusual structural elements, G-quadruplexes, which are responsible for the cis-acting regulation of viral mRNA translation. By studying the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1) mRNA, we demonstrate that destabilization of G-quadruplexes using antisense oligonucleotides increases EBNA1 mRNA translation. In contrast, pretreatment with a G-quadruplex-stabilizing small molecule, pyridostatin, decreases EBNA1 synthesis, highlighting the importance of G-quadruplexes within virally encoded transcripts as unique regulatory signals for translational control and immune evasion. Furthermore, these findings suggest alternative therapeutic strategies focused on targeting RNA structure within viral ORFs.

    Original languageEnglish
    Pages (from-to)358-364
    Number of pages7
    JournalNature Chemical Biology
    Volume10
    Issue number5
    DOIs
    Publication statusPublished - May 2014

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