Dual Short Upstream Open Reading Frames Control Translation of a Herpesviral Polycistronic mRNA

The Kaposi's sarcoma-associated herpesvirus (KSHV) protein kinase, encoded by ORF36, functions to phosphorylate cellular and viral targets important in the KSHV lifecycle and to activate the anti-viral prodrug ganciclovir. Unlike the vast majority of mapped KSHV genes, no viral transcript has been identified with ORF36 positioned as the 5′-proximal gene. Here we report that ORF36 is robustly translated as a downstream cistron from the ORF35–37 polycistronic transcript in a cap-dependent manner. We identified two short, upstream open reading frames (uORFs) within the 5′ UTR of the polycistronic mRNA. While both uORFs function as negative regulators of ORF35, unexpectedly, the second allows for the translation of the downstream ORF36 gene by a termination-reinitiation mechanism. Positional conservation of uORFs within a number of related viruses suggests that this may be a common γ-herpesviral adaptation of a host translational regulatory mechanism.

• Publication year

  2013

• Venue

  PLoS Pathogens

• Publication date

  2013-01-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.ppat.1003156PMID 23382684PMCID 3561293
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2010cited by this paper
• KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine.

  2010cited by this paper
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  2010cited by this paper
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  2009influential reference
• IRESite—a tool for the examination of viral and cellular internal ribosome entry sites

  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2009cited by this paper
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  2008cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2007cited by this paper
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  2006cited by this paper
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  2006cited by this paper
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  2006cited by this paper
• Ribosomal shunting mediated by a translational enhancer element that base pairs to 18S rRNA.

  2006cited by this paper
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  2006cited by this paper
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  2000cited by this paper
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  2000cited by this paper
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  2000influential reference
• Translational Control of Viral Gene Expression in Eukaryotes

  2000cited by this paper
• Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) open reading frame 36 protein is a serine protein kinase.

  2000cited by this paper
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