Abstract
Arenavirus and bunyavirus RNA genomes are unusual in that they are found in circular nucleocapsids, presumably due to the annealing of their complementary terminal sequences. Moreover, arenavirus genome synthesis initiates with GTP at position +2 of the template rather than at the precise 3' end (position +1). After formation of a dinucleotide, 5' pppGpC(OH) is then realigned on the template before this primer is extended. The net result of this "prime and realign" mechanism of genome initiation is that 5' pppG is found as an unpaired 5' nucleotide when the complementary genome ends anneal to form a double-stranded (dsRNA) panhandle. Using 5' pppRNA made in vitro and purified so that all dsRNA side products are absent, we have determined that both this 5' nucleotide overhang, as well as mismatches within the dsRNA (as found in some arenavirus genomes), clearly reduce the ability of these model dsRNAs to induce interferon upon transfection into cells. The presence of this unpaired 5' ppp-nucleotide is thus another way that some viruses appear to use to avoid detection by cytoplasmic pattern recognition receptors.
Highlights
Transcripts whose 5Ј ends were at position Ϫ1 [2]
As the sequence 3Ј OHGCG... is present at all arenavirus genome and antigenome 3Ј ends, we proposed that TCRV genomes were initiated by 5Ј pppGpCOH formed at an internal position of the 3Ј OHGCG... sequence (Fig. 1)
As the Hantaan (bunya)virus (HTN) RdRP cap-dependent endonuclease strongly prefers to cleave host mRNAs after guanosines to generate capped fragments that prime viral mRNA synthesis, we originally proposed that HTN genome replication initiated with pppG opposite the C at position ϩ3 (3Ј OHUACUACUAC...), and following the addition of a few nucleotides, the uncapped primer, e.g. pppGAUGOH, realigns at the genome 3Ј end creating an extra overhanging 5Ј pppG
Summary
Transcripts whose 5Ј ends were at position Ϫ1 (see Fig. 1) [2]. As the sequence 3Ј OHGCG... is present at all arenavirus genome and antigenome 3Ј ends, we proposed that TCRV genomes were initiated by 5Ј pppGpCOH (an uncapped primer) formed at an internal position (in bold) of the 3Ј OHGCG... sequence (Fig. 1). Model Arenavirus dsRNA Panhandle Structures Are Poor PAMPs—As mentioned above, two groups have recently reported that chemically synthesized 5Ј ppp-ssRNA by itself does not induce IFN via RIG-I, but becomes active when annealed to a complementary RNA.
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