Article

Influenza virus inhibits RNA polymerase II elongation

Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Virology (Impact Factor: 3.32). 08/2006; 351(1):210-7. DOI: 10.1016/j.virol.2006.03.005
Source: PubMed

ABSTRACT

The influenza virus RNA-dependent RNA polymerase interacts with the serine-5 phosphorylated carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (Pol II). It was proposed that this interaction allows the viral RNA polymerase to gain access to host mRNA-derived capped RNA fragments required as primers for the initiation of viral mRNA synthesis. Here, we show, using a chromatin immunoprecipitation (ChIP) analysis, that similar amounts of Pol II associate with Pol II promoter DNAs in influenza virus-infected and mock-infected cells. However, there is a statistically significant reduction in Pol II densities in the coding region of Pol II genes in infected cells. Thus, influenza virus specifically interferes with Pol II elongation, but not Pol II initiation. We propose that influenza virus RNA polymerase, by binding to the CTD of initiating Pol II and subsequent cleavage of the capped 5' end of the nascent transcript, triggers premature Pol II termination.

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    • "vRNPs are first transcribed by the vRNP-associated polymerase in a reaction primed by 5 capped 10–13nt RNAs that are derived from cellular pre-mRNAs through the polymerase cap-binding and endonucleolytic activities (reviewed in Fodor, 2013). Viral mRNA synthesis is therefore dependent on the activity of host RNA polymerase II and can thus be inhibited by drugs that target cellular transcription (Chan et al., 2006; Hay et al., 1977; Mark et al., 1979; Vreede et al., 2011). The viral polymerase is also responsible for polyadenylating the 3 end of viral transcripts, following which they are exported to the cytoplasm for viral protein expression. "
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    • "Alpha-amanitin inhibits both RNA polymerase II initiation and elongation (39) and thus, like ActD, prevents synthesis of viral mRNA, cRNA, and vRNA (33, 34). In contrast, the RNA polymerase II elongation inhibitor 5,6-dichloro-1-β-d-ribofuranosyl-benzimidazole (DRB) (40, 41) does not affect primary viral transcription but inhibits cRNA and vRNA synthesis (and therefore secondary viral transcription) (42) by preventing the nuclear export of viral transcripts (23, 43). Consistent with previous publications, no viral mRNA, cRNA, or vRNA synthesis can be detected in infected cells following treatment with either α-amanitin or ActD (Fig. 6A). "
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    • "It has been suggested that this may increase the efficiency of the cap-snatching process, as well as linking viral transcription to cellular pathways of mRNA processing and nuclear export [16] [17] [18]. It has also been shown that this interaction increases the efficiency of host shutoff as the viral polymerase not only inhibits Pol II elongation but causes it to be degraded [15] [19] [20], a mechanism that appears to contribute to virulence [21]. As viral transcription, but not replication , is dependent on Pol II-generated capped transcripts, the suppression of Pol II synthesis as infection proceeds may contribute to the decline in viral mRNA synthesis late in infection [16]. "
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