Journal
NATURE MICROBIOLOGY
Volume 1, Issue 5, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NMICROBIOL.2016.29
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Funding
- Wellcome Trust [098721/Z/12/Z]
- Netherlands Organization for Scientific Research (NWO) [825.11.029]
- Medical Research Council (MRC) [MR/K000241/1]
- European Commission [FP7/2007-2013 HEALTH-F4-2008-201418]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J001694/1]
- Lincoln College Oxford
- Biotechnology and Biological Sciences Research Council [BB/J001694/1, BB/J001694/2] Funding Source: researchfish
- Medical Research Council [MR/K000241/1] Funding Source: researchfish
- Wellcome Trust [098721/Z/12/Z] Funding Source: Wellcome Trust
- BBSRC [BB/J001694/1, BB/J00054X/1, BB/J001694/2] Funding Source: UKRI
- MRC [MR/N010744/1, MR/K000241/1] Funding Source: UKRI
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RNA-dependent RNA polymerases (RdRps) are used by RNA viruses to replicate and transcribe their RNA genomes(1). They adopt a closed, right-handed fold with conserved subdomains called palm, fingers and thumb(1,2). Conserved RdRp motifs A-F coordinate the viral RNA template, NTPs and magnesium ions to facilitate nucleotide condensation(1). For the initiation of RNA synthesis, most RdRps use either a primer-dependent or de novo mechanism(3). The influenza Avirus RdRp, in contrast, uses a capped RNA oligonucleotide to initiate transcription, and a combination of terminal and internal de novo initiation for replication(4). To understand how the influenza A virus RdRp coordinates these processes, we analysed the function of a thumb subdomain beta-hairpin using initiation, elongation and single-molecule Forster resonance energy transfer (sm-FRET) assays. Our data indicate that this beta-hairpin is essential for terminal initiation during replication, but not necessary for internal initiation and transcription. Analysis of individual residues in the tip of the beta-hairpin shows that PB1 proline 651 is critical for efficient RNA synthesis in vitro and in cell culture. Overall, this work advances our understanding of influenza A virus RNA synthesis and identifies the initiation platform of viral replication.
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