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fredag 21 november 2014

(2) EBOV ja MARV RNA editointi (jatkoa) . Uusinta käsitystä asiasta.


The recent outbreak in West Africa of Zaire ebolavirus (EBOV) is of unprecedented scope in terms of the number of cases and geographic breadth (1). This event, coupled with the increased frequency of
outbreaks caused by the Filoviridae family, which includes the ebolaviruses and marburgviruses (MARV), highlights the need for a complete understanding of filovirus replication (2,4).

Previous studies have provided a detailed description of EBOV and MARV genome transcription and replication strategies (5,7). The filoviruses possess nonsegmented negative-sense (NNS) viral RNA (vRNA) genomes of approximately 19 kb in length. 

Filoviral genome replication results in the production of full-length, positive-sense antigenomic RNA and negative-sense genomic RNA (7, 8).

 In contrast, filovirus transcription likely proceeds along the viral genomic RNA template via a stop-start mechanism that results in the production of individual 5′-7-methylguanosine (m7G)-capped, 3′-polyadenylated mRNAs (9,11). This is analogous to the transcription of several other NNS RNA viruses, such as vesicular stomatitis virus (VSV) (12).

 Transcripts are produced from each of the nucleoprotein (NP), VP35, VP40, viral glycoprotein (GP), VP30, VP24, and large (L) protein genes. 

For EBOV, there are seven transcription start signals of 12 nucleotides (nt) in length that differ at only 1 nt; transcriptional stop signals are present for each gene and are also conserved, and each gene possesses, on the genomic vRNA, a poly(U) stretch that serves as a signal for polyadenylation (6).

 Notably, the VP24/L junction contains two stop signals (13), but most transcription stops at the first stop signal (14).

 For MARV, the transcriptional start signals are also 12 nt in length with minor variations depending on the specific gene, and the consensus stop signal is also conserved. Between NNS RNA virus start and stop sequences are intergenic regions that differ in length.

Whereas most filoviral genes have been reported to yield a single mRNA species encoding a single major translation product, the EBOV GP gene is an exception. The major mRNA species produced by the GP gene encodes soluble glycoprotein (sGP). However, two additional proteins, the full-length GP (a structural protein that serves as the viral attachment and fusion protein) and ssGP (a protein of unknown function) are produced via an RNA editing process.

This RNA editing is carried out by the viral polymerase, such that one or more non-template-encoded A nucleotides are inserted within the EBOV GP open reading frame (ORF) at a stretch of seven U nucleotides spanning genome positions 6918 to 6925 (15, 16).

Therefore, RNA editing by the viral polymerase increases the number of proteins produced by a limited number of viral genes (17, 18).

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