Determinants that govern alternative splicing of parvovirus pre-mRNAs

Pintel, David J.; Gersappe, Anand; Haut, Don; Pearson, James L.

doi:10.1006/smvy.1995.0034

Cited by 22 publications

(29 citation statements)

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“…Differences between MVMi and MVMp in this area have been previously noted, and ways in which these differences might affect RNA processing in the two strains have been discussed previously (19). Recently, two reports have indicated that mutations that increase relative levels of NS2 by enhancing the excision of the large intron lead to increased replication of MVMi in murine fibroblasts (A.…”

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confidence: 90%

“…Previous studies in our lab have shown that even minor alterations of the MVM large-intron 3Ј splice site can have significant effects on the steady-state ratio of R1 to R2 and, hence, on the ratio of the viral nonstructural proteins NS1 and NS2 (19,28). Differences between MVMi and MVMp in this area have been previously noted, and ways in which these differences might affect RNA processing in the two strains have been discussed previously (19).…”

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confidence: 95%

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Replication of Minute Virus of Mice DNA Is Critically Dependent on Accumulated Levels of NS2

Choi

Newman

Burger

et al. 2005

J Virol

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Following transfection of murine fibroblasts, the lymphotropic strain of minute virus of mice (MVMi) does not efficiently produce progeny single-strand DNA (ssDNA). However, changing a single nucleotide in the MVMi 3 splice site to that found in the fibrotropic strain MVMp enabled full DNA replication and production of ssDNA. This change enhanced excision of the large intron and the production of NS2, likely by improving interaction, in fibroblasts with the branch point-binding U2 snRNA. One function of NS2 involves interaction with the nuclear export protein Crm1. The defect in production of MVMi ssDNA in fibroblasts can also be overcome by introducing a mutation in MVMi NS2 that enhances its interaction with Crm1. Although MVMi contains a 3 splice site that performs poorly in fibroblasts, MVMi generated at least as much R2 and NS2 in murine lymphocytes as did MVMp in fibroblasts. Therefore, it appears that MVMp has acquired a mutation that improves the excision of the large intron, as it adapted to fibroblasts to accommodate the need for NS2 for replication in these cells, and that the ratio of NS1 to NS2 may play a larger role in the host range of MVM than previously appreciated.Two strains of minute virus of mice, fibrotropic strain MVMp and lymphotropic strain MVMi, are reciprocally restricted for growth in murine cells (2,10,15,23,25,26). MVMp productively infects murine fibroblasts but not murine lymphocytes, while MVMi does the opposite. The major viral determinant of this host range resides within the capsid. The primary block to restrictive infections is intracellular, following binding to cells but before deposition of viral DNA in the nucleus (1,3,4,11,12,20).Characterization of MVMp and MVMi has also led to the identification of another determinant that affects viral replication in a host cell-dependent manner. Analysis of MVMi virus selected for growth on fibroblasts and analysis of the replication of engineered MVMi and MVMp chimeras on murine lymphocytes have demonstrated that a region encompassing the large-intron 3Ј splice site and P38 TATA box also plays a role in the efficiency of viral DNA replication in these two cell types (7, 12). The role that this region plays in replication has not been well characterized, but in both cases, differences in the ratio of mRNA R1 to R2, which encode NS1 and NS2, respectively, have been observed (4, 7, 11). The importance of the NS region in cell type-specific replication has also been noted for cells of neuronal origin (22).Previous studies in our lab have shown that even minor alterations of the MVM large-intron 3Ј splice site can have significant effects on the steady-state ratio of R1 to R2 and, hence, on the ratio of the viral nonstructural proteins NS1 and NS2 (19,28). Differences between MVMi and MVMp in this area have been previously noted, and ways in which these differences might affect RNA processing in the two strains have been discussed previously (19). Recently, two reports have In this study we have shown that, following transfection of mur...

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Replication of Minute Virus of Mice DNA Is Critically Dependent on Accumulated Levels of NS2

Choi

Newman

Burger

et al. 2005

J Virol

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“…Transcripts R1 and R2 are generated from a promoter (P4) at map unit 4 and encode the viral nonstructural proteins NS1 and NS2, respectively, while the R3 transcripts are generated from a promoter (P38) at map unit 38 and encode the viral capsid proteins (12,39). Both NS1 and NS2 play essential roles in viral replication and cytotoxicity (13), and so maintenance of their relative steadystate levels, which is controlled at least partially by alternative splicing (40), is critical to the MVM life cycle. All MVM mRNAs generated during infection or following transfection are very stable (43).…”

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“…All MVM mRNAs generated during infection or following transfection are very stable (43). The alternative splicing of MVM premRNAs is accomplished solely by the interactions between cellular factors and viral cis-acting signals (40).…”

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A Premature Termination Codon Interferes with the Nuclear Function of an Exon Splicing Enhancer in an Open Reading Frame-Dependent Manner

Gersappe

Pintel

1999

Molecular and Cellular Biology

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Premature translation termination codon (PTC)-mediated effects on nuclear RNA processing have been shown to be associated with a number of human genetic diseases; however, how these PTCs mediate such effects in the nucleus is unclear. A PTC at nucleotide (nt) 2018 that lies adjacent to the 5 element of a bipartite exon splicing enhancer within the NS2-specific exon of minute virus of mice P4 promoter-generated pre-mRNA caused a decrease in the accumulated levels of P4-generated R2 mRNA relative to P4-generated R1 mRNA, although the total accumulated levels of P4 product remained the same. This effect was seen in nuclear RNA and was independent of RNA stability. The 5 and 3 elements of the bipartite NS2-specific exon enhancer are redundant in function, and when the 2018 PTC was combined with a deletion of the 3 enhancer element, the exon was skipped in the majority of the viral P4-generated product. Such exon skipping in response to a PTC, but not a missense mutation at nt 2018, could be suppressed by frame shift mutations in either exon of NS2 which reopened the NS2 open reading frame, as well as by improvement of the upstream intron 3 splice site. These results suggest that a PTC can interfere with the function of an exon splicing enhancer in an open reading frame-dependent manner and that the PTC is recognized in the nucleus.Premature termination codons (PTCs) decrease the accumulated levels of most known mRNAs in which they reside (reviewed in reference 28). In the yeast Saccharomyces cerevisiae, the UPF genes are involved in the degradation of PTCcontaining RNAs in the cytoplasm (review in reference 37). Similarly, the SMG proteins of Caenorhabditis elegans are required for the rapid decay of PTC-containing unc-54 myosin heavy-chain mRNAs (reviewed in reference 41).PTC-mediated effects on nuclear RNA processing have been shown to be associated with a number of human genetic diseases (reviewed in references 28 and 29); however, how PTCs mediate such effects in the nucleus is still unclear. In mammalian cells, PTCs have been shown to decrease the levels of nucleus-associated mRNAs by a posttranscriptional mechanism, often attributed to mRNA decay (3,6,9,28,45). Experiments done with PTCs in the human TPI gene suggest that nonsense-mediated decay (NMD) occurs on a fully spliced nucleus-associated mRNA molecule, possibly during mRNA export to the cytoplasm (4, 5, 9, 28).There is also increasing evidence that PTCs may affect mammalian RNA processing events other than decay. For example, several instances of PTC-associated exon skipping have been described (15,19,28,33). Perhaps the best-studied example is skipping of the 66-nucleotide (nt) exon 51 of fibrillin FBN1 RNA, which was detected when nonsense but not missense mutations were present within this exon, which was independent of protein synthesis, and for which normal splicing was restored when the nonsense codon was shifted out of frame with the initiation codon (14, 23). Retention of introns upstream of PTC-containing exons has also been reported for P4-ge...

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“…The compact genomes of parvoviruses, except for the largest densoviruses, increase their coding capacity from overlapping reading frames by using alternative splicing. Both elements in introns Acta Veterinaria Hungarica 47, 1999 and exons govern these processes in a cis-acting fashion (Pintel et al, 1995).…”

Section: Parvovirus Infection and Replicationmentioning

confidence: 99%

Molecular and Structural Basis of the Evolution of Parvovirus Tropism

Tijssen¹

1999

Acta Veterinaria Hungarica

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Determinants that govern alternative splicing of parvovirus pre-mRNAs

Cited by 22 publications

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Replication of Minute Virus of Mice DNA Is Critically Dependent on Accumulated Levels of NS2

Replication of Minute Virus of Mice DNA Is Critically Dependent on Accumulated Levels of NS2

A Premature Termination Codon Interferes with the Nuclear Function of an Exon Splicing Enhancer in an Open Reading Frame-Dependent Manner

Molecular and Structural Basis of the Evolution of Parvovirus Tropism

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