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Nat Chem Biol. 2014 May;10(5):358-64. doi: 10.1038/nchembio.1479. Epub 2014 Mar 16.

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

Author information

1
Department of Chemistry, University of Cambridge, Cambridge, UK.
2
1] Tumour Immunology, Department of Immunology, Clive Berghofer Cancer Research Centre, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. [2] QIMR Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
3
Centre for Synchrotron Science, Monash University, Melbourne, Victoria, Australia.
4
Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
5
1] Department of Chemistry, University of Cambridge, Cambridge, UK. [2] Cambridge Institute, Cancer Research UK, Li Ka Shing Center, Cambridge, UK. [3] School of Clinical Medicine, The University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, UK.

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.

PMID:
24633353
PMCID:
PMC4188979
DOI:
10.1038/nchembio.1479
[Indexed for MEDLINE]
Free PMC Article

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