D Kolakofsky

Osaka Prefectural Institute of Public Health, Ōsaka, Ōsaka, Japan

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Publications (86)470.94 Total impact

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    O Gubbay, J Curran, D Kolakofsky
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    ABSTRACT: A cell-free system for studying Sendai virus RNA synthesis was reconstituted from N protein:RNA templates and transfected cell extracts in which the viral N, P and L proteins were expressed. Both transcription (mRNA synthesis) and replication (genome and antigenome synthesis) took place concurrently in these reactions. Viral RNA polymerases engaged in replication (replicases) were found to elongate their chains at a constant speed along the genome (1.7 nt/s), in a highly processive manner. In contrast, viral RNA polymerases engaged in transcription (transcriptases), although capable of synthesizing RNA at a comparable speed to replicases, were poorly processive. In this system, therefore, transcriptases require special reaction conditions to promote processivity that are not required by replicases. In addition, during replication, incomplete nascent genome chains were shown to be assembled with N protein, providing direct evidence that the synthesis and assembly of genomes are concurrent events. The strong processivity of replicases, independent of the reaction conditions, may thus be due to the coupling of genome synthesis and assembly. A model is proposed to explain how pausing of viral polymerase on the template is restricted when assembly and synthesis of the nascent chain are coupled.
    Journal of General Virology 01/2002; 82(Pt 12):2895-903. · 3.53 Impact Factor
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    D Garcin, J Curran, M Itoh, D Kolakofsky
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    ABSTRACT: The Sendai virus (SeV) C gene codes for a nested set of four C proteins that carry out several functions, including the modulation of viral RNA synthesis and countering of the cellular antiviral response. Using mutant C genes (and in particular a C gene with a deletion of six amino acids present only in the larger pair of C proteins) and recombinant SeV carrying these mutant C genes, we find that the nested set of C proteins carry out a nested set of functions. All of the C proteins interdict interferon (IFN) signaling to IFN-stimulated genes (ISGs) and prevent pY701-Stat1 formation. However, only the larger C proteins can induce STAT1 instability, prevent IFN from inducing an antiviral state, or prevent programmed cell death. Remarkably, interdiction of IFN signaling to ISGs and the absence of pY701-Stat1 formation did not prevent IFN-alpha from inducing an anti-Vesicular stomatitis virus (VSV) state. It is possible that IFN-alpha signaling to induce an anti-VSV state can occur independently of the well-established Jak/Stat/ISGF3 pathway and that it is this parallel pathway that is targeted by the longer C proteins.
    Journal of Virology 09/2001; 75(15):6800-7. DOI:10.1128/JVI.75.15.6800-6807.2001 · 4.65 Impact Factor
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    D Garcin, J Curran, D Kolakofsky
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    ABSTRACT: Sendai virus (SeV) infection of interferon (IFN)-competent cells is one of the most efficient ways of inducing IFN production. Virus replication is nevertheless largely unaffected, since SeV infection also interfers with IFN action, a prerequisite for the establishment of an antiviral state. This property has been mapped by reverse genetics to the viral C gene, which is also known to act as a promoter-specific inhibitor of viral RNA synthesis. Using luciferase reporter plasmids containing IFN-responsive promoters, we have found that all four C proteins effectively interdict IFN signaling when expressed independently of SeV infection. The C proteins must therefore interact directly with cellular components to carry this out. The C gene in the context of an SeV infection was also found to induce STAT1 instability in some cells, whereas in other cells it apparently acts to prevent the synthesis of STAT1 in response to the virus infection or IFN treatment. The SeV C proteins appear to act in at least two ways to counteract the IFN induced by SeV infection.
    Journal of Virology 11/2000; 74(19):8823-30. DOI:10.1128/JVI.74.19.8823-8830.2000 · 4.65 Impact Factor
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    D Garcin, P Latorre, D Kolakofsky
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    ABSTRACT: We have studied the relationship between the Sendai virus (SeV) C proteins (a nested set of four proteins initiated at different start codons) and the interferon (IFN)-mediated antiviral response in IFN-competent cells in culture. SeV strains containing wild-type or various mutant C proteins were examined for their ability (i) to induce an antiviral state (i.e., to prevent the growth of vesicular stomatitis virus [VSV] following a period of SeV infection), (ii) to induce the elevation of Stat1 protein levels, and (iii) to prevent IFN added concomitant with the SeV infection from inducing an antiviral state. We find that expression of the wild-type C gene and, specifically, the AUG114-initiated C protein prevents the establishment of an antiviral state: i.e., cells infected with wild-type SeV exhibited little or no increase in Stat1 levels and were permissive for VSV replication, even in the presence of exogenous IFN. In contrast, in cells infected with SeV lacking the AUG114-initiated C protein or containing a single amino acid substitution in the C protein, the level of Stat1 increased and VSV replication was inhibited. The prevention of the cellular IFN-mediated antiviral response appears to be a key determinant of SeV pathogenicity.
    Journal of Virology 09/1999; 73(8):6559-65. · 4.65 Impact Factor
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    S Hausmann, D Garcin, C Delenda, D Kolakofsky
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    ABSTRACT: Paramyxoviruses cotranscriptionally edit their P gene mRNAs by expanding the number of Gs of a conserved AnGn run. Different viruses insert different distributions of guanylates, e.g., Sendai virus inserts a single G, whereas parainfluenza virus type 3 inserts one to six Gs. The sequences conserved at the editing site, as well as the experimental evidence, suggest that the insertions occur by a stuttering process, i.e., by pseudotemplated transcription. The number of times the polymerase "stutters" at the editing site before continuing strictly templated elongation is directed by a cis-acting sequence found upstream of the insertions. We have examined the stuttering process during natural virus infections by constructing recombinant Sendai viruses with mutations in their cis-acting sequences. We found that the template stutter site is precisely determined (C1052) and that a relatively short region (approximately 6 nucleotides) just upstream of the AnGn run can modulate the overall frequency of mRNA editing as well as the distribution of the nucleotide insertions. The positions more proximal to the 5' AnGn run are the most important in this respect. We also provide evidence that the stability of the mRNA/template hybrid plays a determining role in the overall frequency and range of mRNA editing. When the template U run is extended all the way to the stutter site, adenylates rather than guanylates are added at the editing site and their distribution begins to resemble the polyadenylation associated with mRNA 3' end formation by the viral polymerase. Our data suggest how paramyxovirus mRNA editing and polyadenylation are related mechanistically and how editing sites may have evolved from poly(A)-termination sites or vice versa.
    Journal of Virology 08/1999; 73(7):5568-76. · 4.65 Impact Factor
  • J Curran, D Kolakofsky
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    ABSTRACT: Molecular studies on the replication of paramyxoviruses have undergone a revolution in recent years due to the development of techniques that permit the manipulation of their genomes as cDNA. This has led to new information on the structure-function organization of the viral proteins involved in genome expression, as well as dissection of the cis-acting template sequences that regulate transcription and replication. Studies using recombinant viruses have also provided new insights into the role of the accessory proteins (V, C, M1/M2) in both for virus growth in cultured cells and pathogenesis in animals.
    Advances in Virus Research 02/1999; 54:403-22. DOI:10.1016/S0065-3527(08)60373-5 · 3.59 Impact Factor
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    S Hausmann, D Garcin, A S Morel, D Kolakofsky
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    ABSTRACT: Editing of paramyxovirus P gene mRNAs occurs cotranscriptionally and functions to fuse an alternate downstream open reading frame to the N-terminal half of the P protein. G residues are inserted into a short G run contained within a larger purine run (AnGn) in this process, by a mechanism whereby the transcribing polymerase stutters (i.e., reads the same template cytosine more than once). Although Sendai virus (SeV) and bovine parainfluenza virus type 3 (bPIV3) are closely related, the G insertions in their P mRNAs are distributed differently. SeV predominantly inserts a single G residue within the G run of the sequence 5' AACAAAAAAGGG, whereas bPIV3 inserts one to six G's at roughly equal frequency within the sequence 5' AUUAAAAAAGGGG (differences are underlined). We have examined how the cis-acting editing sequence determines the number of G's inserted, both in a transfected cell system using minigenome analogues and by generating recombinant viruses. We found that the presence of four rather than three G's in the purine run did not affect the distribution of G insertions. However, when the underlined AC of the SeV sequence was replaced by the UU found in bPIV3, the editing phenotype from both the minigenome and the recombinant virus resembled that found in natural bPIV3 infections (i.e., a significant fraction of the mRNAs contained two to six G insertions). The two nucleotides located just upstream of the polypurine tract are thus key determinants of the editing phenotype of these viruses. Moreover, the minimum number of A residues that will promote SeV editing phenotype is six but can be reduced to five when the upstream AC is replaced by UU. A model for how the upstream dinucleotide controls the insertion phenotype is presented.
    Journal of Virology 02/1999; 73(1):343-51. · 4.65 Impact Factor
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    P Latorre, D Kolakofsky, J Curran
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    ABSTRACT: The Sendai virus P/C mRNA expresses eight primary translation products by using a combination of ribosomal choice and cotranscriptional mRNA editing. The longest open reading frame (ORF) of the mRNA starts at AUG104 (the second initiation site) and encodes the 568-amino-acid P protein, an essential subunit of the viral polymerase. The first (ACG81), third (ATG114), fourth (ATG183), and fifth (ATG201) initiation sites are used to express a C-terminal nested set of polypeptides (collectively named the C proteins) in the +1 ORF relative to P, namely, C', C, Y1, and Y2, respectively. Leaky scanning accounts for translational initiation at the first three start sites (a non-ATG followed by ATGs in progressively stronger contexts). Consistent with this, changing ACG81/C' to ATG (GCCATG81G) abrogates expression from the downstream ATG104/P and ATG114/C initiation codons. However, expression of the Y1 and Y2 proteins remains normal in this background. We now have evidence that initiation from ATG183/Y1 and ATG201/Y2 takes place via a ribosomal shunt or discontinuous scanning. Scanning complexes appear to assemble at the 5' cap and then scan ca. 50 nucleotides (nt) of the 5' untranslated region before being translocated to an acceptor site at or close to the Y initiation codons. No specific donor site sequences are required, and translation of the Y proteins continues even when their start codons are changed to ACG. Curiously, ATG codons (in good contexts) in the P ORF, placed either 16 nt upstream of Y1, 29 nt downstream of Y2, or between the Y1 and Y2 codons, are not expressed even in the ACGY1/ACGY2 background. This indicates that ATG183/Y1 and ATG201/Y2 are privileged start sites within the acceptor site. Our observations suggest that the shunt delivers the scanning complex directly to the Y start codons.
    Molecular and Cellular Biology 10/1998; 18(9):5021-31. · 5.04 Impact Factor
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    P Latorre, T Cadd, M Itoh, J Curran, D Kolakofsky
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    ABSTRACT: Recombinant Sendai viruses were prepared which cannot express their Cprime, C, or Cprime plus C proteins due to mutation of their respective start codons ([Cprime-minus], [C-minus] and [double mutant], respectively). The [Cprime-minus] and [C-minus] stocks were similar to that of wild-type (wt) virus in virus titer and plaque formation, whereas the double-mutant stock had a much-reduced PFU or 50% egg infective dose/particle ratio and produced very small plaques. Relative to the wt virus infection, the [Cprime-minus] and [C-minus] infections of BHK cells resulted in significantly greater accumulation of viral RNAs, consistent with the known inhibitory effects of the Cprime and C proteins. The double-mutant infection, in contrast, was delayed in its accumulation of viral RNAs; however, once accumulation started, overaccumulation quickly occurred, as in the single-mutant infections. Our results suggest that the Cprime and C proteins both provide a common positive function early in infection, so that only the double mutant undergoes delayed RNA accumulation and exhibits the highly debilitated phenotype. Later in infection, the same proteins appear to act as inhibitors of RNA accumulation. In infections of mice, [Cprime-minus] was found to be as virulent as wt virus whereas [C-minus] was highly attenuated. These results suggest that the Cprime and C proteins cannot be functionally equivalent, since C can replace Cprime for virulence in mice whereas Cprime cannot replace C.
    Journal of Virology 08/1998; 72(7):5984-93. · 4.65 Impact Factor
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    Journal of Virology 03/1998; 72(2):891-9. · 4.65 Impact Factor
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    ABSTRACT: The role of the negative-stranded virus accessory C proteins is difficult to assess because they appear sometimes as nonessential and thereby of no function. On the other hand, when a function is found, as in the case of Sendai virus, it represents an enigma, in that the C proteins inhibit replication under conditions where the infection follows an exponential course. Furthermore, this inhibitory function is exerted differentially: in contrast to the replication of internal deletion defective interfering (DI) RNAs, that of copy-back DI RNAs appears to escape inhibition, under certain experimental conditions (in vivo assay). In a reexamination of the C effect by the reverse genetics approach, it was found that copy-back RNA replication is inhibited by C in vivo as well, under conditions where the ratio of C to copy-back template is increased. This effect can be reversed by an increase in P but not L protein. The "rule of six" was differentially observed in the presence or absence of C. Finally, a difference in the ability of the replicating complex to tolerate promoter modifications in RNA synthesis initiation was shown to occur in the presence or the absence of C as well. We propose that C acts by increasing the selectivity of the replicating complex for the promoter cis-acting elements governing its activity. The inhibitory effect of C becomes the price to pay for this increased selectivity.
    Journal of Virology 01/1998; 71(12):9588-99. · 4.65 Impact Factor
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    S Hausmann, J P Jacques, D Kolakofsky
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    ABSTRACT: Paramyxoviruses cotranscriptionally edit their P gene mRNA by the programmed insertion of G residues into a short G run contained within a larger purine run, via pseudo-templated transcription. The templates for paramyxovirus transcription are genome nucleocapsids in which each nucleoprotein subunit is associated with 6 nt, and only genomes whose lengths are multiples of 6 are found naturally or are replicated efficiently in transfected cell systems. We have examined the effect of varying total genome length on the frequency and number of insertions into the mRNA editing site in a transfected cell system, using constructs that generate mini-genome analogues. We found that, as long as the purine run sequence and the region immediately upstream were unaltered, editing occurred during mRNA synthesis independent of the precise length of the minigenome. However, when mini-genome constructs whose lengths were not multiples of 6 were used, insertions (or deletions) occurred during antigenome synthesis within the purine run, which strikingly restored the hexamer length. Genome length correction due to changes in the antigenome purine run length occurred only when the mini-genome was not a multiple of 6, and these changes were only poorly affected by mutations in the mRNA editing site and the region immediately upstream. Our results suggest that the mRNA editing site is a natural hotspot for viral polymerase slippage during genome replication, and that this site serves the dual and complementary function of maintaining hexamer genome length. The unusual requirement of paramyxoviruses for genomes of precise hexamer length may have evolved to maintain genome stability against insertions in the mRNA editing site during replication.
    RNA 11/1996; 2(10):1033-45. · 4.62 Impact Factor
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    ABSTRACT: Many paramyxoviruses express small basic C proteins, from an alternate, overlapping open reading frame of the P gene mRNA, which were previously found to inhibit mRNA synthesis. During recent experiments in which infectious Sendai virus (SeV) was recovered from cDNA via the initial expression of the viral N, P, and L genes from plasmids, the abrogation of C protein expression from the plasmid P gene was found to be necessary for virus recovery. We have investigated the effect of C coexpression on the amplification of an internally deleted defective interfering (DI) genome directly in the transfected cell, for which, in contrast to virus recovery experiments, genome amplification is independent of mRNA synthesis carried out by the SeV polymerase. We find that C protein coexpression also strongly inhibits the amplification of this DI genome but has little or no effect on that of a copy-back DI genome (DI-H4). We have also characterized the C protein from a mutant SeV and found that (i) it had lost most of its inhibitory activity on internally deleted DI genome amplification and (ii) its coexpression no longer prevented the recovery of SeV from DNA. However, consistent with the insensitivity of copy-back DI genomes to C protein inhibition, C coexpression did not prevent the recovery of copy-back nondefective viruses from DNA. The inhibitory effects of C coexpression thus appear to be promoter specific.
    Journal of Virology 09/1996; 70(8):5067-74. · 4.65 Impact Factor
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    ABSTRACT: We have recovered infectious Sendai virus (SeV) from full-length cDNA (FL-3) by transfecting this cDNA and pGEM plasmids expressing the nucleocapsid protein (NP), phosphoprotein and large proteins into cells infected with a vaccinia virus which expresses T7 RNA polymerase. These cells were then injected into chicken eggs, in which SeV grows to very high titers. FL-3 was marked with a BglII site in the leader region and an NsiI site (ATGCAT) in the 5' nontranslated region of the NP gene, creating a new, out-of-frame, 5' proximal AUG. All the virus stocks generated eventually removed this impediment to NP expression, by either point mutation or recombination between FL-3 and pGEM-NP. The recovery system was found to be highly recombinogenic. Even in the absence of selective pressure, one in 20 of the recombinant SeV generated had exchanged the NP gene of FL-3 with that of pGEM-NP. When a fifth plasmid containing a new genomic 3' end without the presumably deleterious BglII site was included as another target for recombination, the new genomic 3' end was found in the recombinant SeV in 12 out of 12 recoveries. Using this approach, a novel copy-back nondefective virus was generated which interferes with wild-type virus replication.
    The EMBO Journal 01/1996; 14(24):6087-94. · 10.75 Impact Factor
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    ABSTRACT: We examined the 5' ends of Hantaan virus (HTN) genomes and mRNAs to gain insight into the manner in which these chains were initiated. Like those of all members of the family Bunyaviridae described so far, the HTN mRNAs contained 5' terminal extensions that were heterogeneous in both length and sequence, presumably because HTN also "cap snatches" host mRNAs to initiate the viral mRNAs. Unexpectedly, however, almost all of the mRNAs contained a G residue at position -1, and a large fraction also lacked precisely one of the three UAG repeats at the termini. The genomes, on the other hand, commenced with a U residue at position +1, but only 5' monophosphates were found here, indicating that these chains may not have initiated with UTP at this position. Taken together, these unusual findings suggest a prime-and-realign mechanism of chain initiation in which mRNAs are initiated with a G-terminated host cell primer and genomes with GTP, not at the 3' end of the genome template but internally (opposite the template C at position +3), and after extension by one or a few nucleotides, the nascent chain realigns backwards by virtue of the terminal sequence repeats, before processive elongation takes place. For genome initiation, an endonuclease, perhaps that involved in cap snatching, is postulated to remove the 5' terminal extension of the genome, leaving the 5' pU at position +1.
    Journal of Virology 10/1995; 69(9):5754-62. · 4.65 Impact Factor
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    ABSTRACT: Subgenomic RNAs of both polarities corresponding to rice hoja blanca virus (RHBV) ambisense RNA4 were detected in RHBV-infected rice tissues. Total RNA extracted from RHBV-infected and noninfected rice tissues and RNA4 purified from RHBV ribonucleoprotein particles were used as templates for primer extension studies. The RNAs extracted from RHBV-infected tissues contain a population of RNA molecules with 10 to 17 nonviral nucleotides at their 5' end. The RNA-cDNA hybrids resulting from primer extension of such RNA molecules were specifically immunoselected with anti-cap antibodies, indicating that the subgenomic RNAs are capped and probably serve as mRNAs and that the additional nucleotides at their 5' end possibly derive from host mRNAs via a cap-snatching mechanism.
    Journal of Virology 04/1995; 69(3):1951-4. · 4.65 Impact Factor
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    J Curran, J B Marq, D Kolakofsky
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    ABSTRACT: Two domains involved in RNA synthesis have recently been found within the N-terminal 77 amino acids of the Sendai virus P protein. One domain is required for RNA synthesis per se and has properties in common with the transactivation domains of cellular transcription factors. The second domain is thought to be specifically required for the nascent chain assembly step in genome replication. We have further mapped this second domain by the construction of chimeric and deleted P proteins to amino acids 33 to 41 of P and by examining the abilities of these P proteins to support DI genome replication in vivo. Using glycerol gradient sedimentation, we have shown that this domain is required to form a stable complex with unassembled NP (P-NP0) and to prevent NP from assembling illegitimately, i.e., independently of the concurrent assembly of a nascent viral genome. Since the P-NP0 complex represents the functional form of unassembled NP which is delivered to the nascent chain during genome replication, and since amino acids 33 to 41 are not required for the stable interaction of P with the assembled NP of the nucleocapsid, this chaperone function of P is not required for mRNA synthesis or the RNA synthesis step of genome replication.
    Journal of Virology 03/1995; 69(2):849-55. · 4.65 Impact Factor
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    ABSTRACT: La Crosse virus is a member of the Bunyavirus genus in the family Bunyaviridae, viruses with trisegmented RNA genomes of mostly negative polarity composed of large (L), medium (M), and small (S) segments. The sequences of the La Crosse/original M and S RNA segments have been previously characterized. Using reverse transcriptase in conjunction with PCR amplification, we have obtained the nucleotide sequence of the L RNA segment, which encodes the viral polymerase in a single large open reading frame. Comparison of the amino acid sequence of the LAC L protein with the sequence of other polymerases from members of the Bunyaviridae, demonstrated the presence of several conserved motifs, some of which are characteristic of many polymerase proteins. A genetic tree comparing the available polymerase proteins of the Bunyaviridae provides insights into the phylogenetic relationships within this large family. Members of the genus Bunyavirus, which are mosquito-borne and infect mammals, have a closer relationship to the plant viruses represented by tomato spotted wilt virus (Tospovirus genus) than to viruses of other genera in the family Bunyaviridae.
    Virology 02/1995; 206(1):742-5. DOI:10.1016/S0042-6822(95)80001-8 · 3.28 Impact Factor
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    J P Jacques, S Hausmann, D Kolakofsky
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    ABSTRACT: Paramyxoviruses are thought to edit their P gene mRNAs co-transcriptionally, by a mechanism in which the polymerase stutters and reads the same template base more than once. Sendai virus (SeV) and bovine parainfluenza virus type 3 (bPIV3) are closely related viruses, but SeV edits its P gene mRNA with the insertion of a single G residue (at approximately 50% frequency) within the sequence 5' A6G3, whereas bPIV3 inserts 1 to approximately 6 Gs at roughly equal frequency within the sequence 5' A6G4. When SeV synthetic mini-genomes containing either SeV or bPIV3 P gene editing cassettes are expressed from cDNA in cells which are also transfected with the SeV NP, P and L genes, the virus-specific editing patterns were reproduced. Since the bPIV3 editing pattern was reproduced in a system that is otherwise completely SeV, this suggests that all the information for the virus-specific editing patterns is due to the RNA sequence itself. Unexpectedly, the length of the template C run was found to be critical, even though it varies from 3 to 7 nucleotides in length in different viruses. Expanding this template C run first led to attenuation of the insertion phenotype, and then to deletions rather than insertions. A stuttering or slippage model to account for these events has been further refined to include a pressure which displaces the nascent strand in a given direction once it has disengaged from the template, and the similarities of this model to those which account for readthrough of cellular RNA polymerase transcription blocks are discussed.
    The EMBO Journal 12/1994; 13(22):5496-503. · 10.75 Impact Factor
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    R Boeck, D Kolakofsky
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    ABSTRACT: Only rarely do GUG (or CUG or ACG) codons which precede the 5'-proximal AUG function as initiators of protein synthesis, even when they are within a context that contains a purine at position -3 and a G at +4. For example, the upstream GUG of the human parainfluenza virus type 1 (hPIV1) P gene is initiated by ribosomes at high frequency, whereas a seemingly similar GUG codon in the hPIV3 P gene is not used at all. We have examined the reasons for this by expressing chimeric hPIV3/hPIV1 mRNAs, both in vivo and in vitro. A major determinant for efficient GUG utilization was located downstream of the GUG, but this did not appear to be involved in the formation of secondary structure. Rather, the sequence immediately downstream was found to be critical; this determinant was mapped to positions +5 and +6. GUG could be used efficiently for ribosomal initiation when the second codon was GAU but not when it was GUA. Similar results were found when other non-AUG start sites, the Sendai virus P gene ACG and the c-myc-1 CUG, were examined. These results suggest that positions +5 and +6 are important determinants for initiation at non-AUG start sites, and that they are recognized independently of the overall secondary structure of the mRNA.
    The EMBO Journal 09/1994; 13(15):3608-17. · 10.75 Impact Factor

Publication Stats

4k Citations
470.94 Total Impact Points

Institutions

  • 1998–2001
    • Osaka Prefectural Institute of Public Health
      Ōsaka, Ōsaka, Japan
  • 1982–1998
    • University of Geneva
      • • Department of Microbiology and Molecular Medicine (MIMOL)
      • • Faculty of Medicine
      Genève, Geneva, Switzerland
  • 1995
    • University of Ottawa
      • Faculty of Medicine
      Ottawa, Ontario, Canada
  • 1993
    • Max Planck Institute of Biochemistry
      München, Bavaria, Germany