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Virus‐encoded endonucleases: expected and novel functions

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Endonucleases catalyze critical steps in the processing, function, and turnover of many cellular RNAs. It is, therefore, not surprising that a number of viruses encode endonucleases that play important roles in viral gene expression. The virion host shutoff (Vhs) endonuclease of herpes simplex virus, the SOX protein of Kaposi Sarcoma Herpesvirus (KSHV), and the influenza virus PB1 endonuclease have well‐characterized functions that stem from their abilities to cleave RNA. Vhs accelerates turnover of many cellular and viral mRNAs, redirecting the cell from host to viral gene expression, counteracting key elements of the innate immune response, and facilitating sequential expression of different classes of viral genes. SOX reduces synthesis of many host proteins during the lytic phase of KSHV infections. PB1 is a component of the influenza RNA polymerase that snatches capped oligonucleotides from cellular pre‐mRNAs to serve as primers during viral mRNA synthesis. However, all three proteins have important second functions. Vhs stimulates translation of the 3′ cistron of bicistronic mRNAs that have selected cellular internal ribosome entry sites, and stimulates polysome loading and translation of selected viral mRNAs at late times during productive infections. SOX has an alkaline exonuclease activity that is important for processing and maturation of newly synthesized copies of the KSHV genome. The influenza RNA polymerase binds the cap and 5′ region of viral mRNAs and recruits eIF4G and other factors to viral mRNAs, allowing them to be translated under conditions of reduced eIF4E functionality. This review will discuss the novel and expected functions of these viral endonucleases. WIREs RNA 2013, 4:693–708. doi: 10.1002/wrna.1188 This article is categorized under: Translation > Translation Mechanisms RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

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Two models for targeting Vhs to its preferred cut sites during translation initiation. The 5′ end of pBK2 mRNA is depicted with the first three AUGs indicated at positions 92, 227, and 269 nucleotides downstream from the cap. The first two AUGs are surrounded by a suboptimal context, compared to the Kozak consensus sequence, and are shown in lower case letters. The third AUG has an optimal Kozak context and is shown in upper case letters. Model A: After loading onto the mRNA by interacting with cap‐bound eIF4F, Vhs reaches at least some of its cut sites by scanning with the 40S ribosomal subunit during translation initiation. Preferred cut sites occur at places where Vhs and the 40S subunit slow down or pause during scanning. These would include sites near the start codon. Vhs reaches cut sites downstream from the first AUG by leaky scanning. Model B: Vhs reaches its cut sites during translation initiation, but does not scan with the 40S ribosomal subunit. After ATP‐independent binding of eIF4E to the cap, multiple copies of eIF4AI/II, eIF4H, and Vhs bind internal sites in the 5′ UTR through a process that is cap‐ and ATP‐dependent. Although not depicted here, a scanning 40S subunit may remodel the mRNA or mRNP structure to create structures that are conducive to Vhs, eIF4AI/II, and eIF4H binding at internal sites.
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Translation > Translation Mechanisms
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability

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