Genomic characterization of a novel virus found in papillomatous lesions from a southern brown bandicoot (Isoodon obesulus) in Western Australia

Bennett, Mark D.; Woolford, Lucy; Stevens, Hans; Ranst, Marc Van; Oldfield, Timothy; Slaven, Mike; O’Hara, A.J.; Warren, K.; Nicholls, P.K.

doi:10.1016/j.virol.2008.03.014

Cited by 36 publications

(22 citation statements)

References 27 publications

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“…We note that we cannot rule out that additional promoters and transcripts may be used to generate this miRNA during some stages of infection. It is interesting to point out that both NCR2 regions of BPCV1 and BPCV2 contain a predicted large T antigen binding site consensus sequence of GAGGC (7,29,46). In addition, our observation that this promoter is robustly active in cells derived from placental mammals suggests it is responsive to transcription factors that were present in the last common ancestor of placental and marsupial mammals.…”

Section: Discussionmentioning

confidence: 83%

“…Our ability to detect the miRNA from the early-orientation construct implies that an intrinsic robust promoter activity is present in the late (papillomavirus) orientation of the BPCV genome that drives expression of BPCV1-miR-B1. Since both the BPCV miRNAs are found within NCR2, and this region is not predicted to encode any proteins (7,46), we speculated that it may serve as a cassette that contains a promoter to drive expression of the primary transcripts that give rise to the BPCV miRNAs. To test this hypothesis, we first subjected the NCR2 sequences from both BPCV1 and BPCV2 to bioinformatic analysis (31) to identify candidate promoter regions ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…In this scenario, these miRNAs would prevent excessive or untimely expression of the T antigens, thereby avoiding the triggering of inappropriate lytic induction or clearance by the adaptive immune response. In this regard, it is interesting to note that a putative T antigen binding site exists in the NCR2 region of both BPCV1 and BPCV2 (7,29,46). Thus, BPCV T antigen could play a role in either a positive or negative feedback loop regulating expression of the miRNA.…”

Section: Discussionmentioning

confidence: 99%

“…The secondary structure of pre-miRNAs were predicted via the mfold RNA folding prediction web server (48). The intrinsic promoters for both BPCV1 and BPCV2 were predicted via the Berkeley Drosophila Genome Project web server (7,46). The noncoding region 2 from BPCV1 and that from BPCV2 were analyzed in the late orientation, with a default minimum promoter cutoff score of 0.80 (between 0 and 1.00).…”

Section: Ethicsmentioning

confidence: 99%

“…Bandicoot papillomatosis carcinomatosis virus types 1 and 2 (BPCV1 and BPCV2) comprise a fascinating group of marsupial viruses that share distinct characteristics of both the Polyomaviridae and Papillomaviridae (7,46). The BPCV viruses encode T antigen early proteins and have a genomic organization similar to that of polyomaviruses.…”

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confidence: 99%

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Insights into Polyomaviridae MicroRNA Function Derived from Study of the Bandicoot Papillomatosis Carcinomatosis Viruses

Chen

Kincaid

Seo

et al. 2011

J Virol

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Several different members of the Polyomaviridae, including some human pathogens, encode microRNAs (miRNAs) that lie antisense with respect to the early gene products, the tumor (T) antigens. These miRNAs negatively regulate T antigen expression by directing small interfering RNA (siRNA)-like cleavage of the early transcripts. miRNA mutant viruses of some members of the Polyomaviridae express increased levels of early proteins during lytic infection. However, the importance of miRNA-mediated negative regulation of the T antigens remains uncertain. Bandicoot papillomatosis carcinomatosis virus type 1 (BPCV1) is associated with papillomas and carcinomas in the endangered marsupial the western barred bandicoot (Perameles bougainville). BPCV1 is the founding member of a new group of viruses that remarkably share distinct properties in common with both the polyomavirus and papillomavirus families. Here, we show that BPCV1 encodes, in the same orientation as the papillomavirus-like transcripts, a miRNA located within a long noncoding region (NCR) of the genome. Furthermore, this NCR serves the function of both promoter and template for the primary transcript that gives rise to the miRNA. Unlike the polyomavirus miRNAs, the BPCV1 miRNA is not encoded antisense to the T antigen transcripts but rather lies in a separate, proximal region of the genome. We have mapped the 3 untranslated region (UTR) of the BPCV1 large T antigen early transcript and identified a functional miRNA target site that is imperfectly complementary to the BPCV1 miRNA. Chimeric reporters containing the entire BPCV1 T antigen 3 UTR undergo negative regulation when coexpressed with the BPCV1 miRNA. Notably, the degree of negative regulation observed is equivalent to that of an identical reporter that is engineered to bind to the BPCV1 miRNA with perfect complementarity. We also show that this miRNA and this novel mode of early gene regulation are conserved with the related BPCV2. Finally, papillomatous lesions from a western barred bandicoot express readily detectable levels of this miRNA, stressing its likely importance in vivo. Combined, the alternative mechanisms of negative regulation of T antigen expression between the BPCVs and the polyomaviruses support the importance of miRNA-mediated autoregulation in the life cycles of some divergent polyomaviruses and polyomavirus-like viruses.MicroRNAs (miRNAs) are small, approximately 22-nucleotide (nt) regulatory RNA molecules that have been shown to play an important role in numerous fields, including virology and immunology (reviewed in references 3, 9, 37, and 43).

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Section: Discussionmentioning

confidence: 83%