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Peptide aptamers that bind to a geminivirus replication protein interfere with viral replication in plant cells.

The AL1 protein of tomato golden mosaic virus (TGMV), a member of the geminivirus family, is essential for viral replication in plants. Its N terminus contains three conserved motifs that mediate origin recognition and DNA cleavage during the initiation of rolling-circle replication. We used the N-terminal domain of TGMV AL1 as bait in a yeast two-hybrid screen of a random peptide aptamer library constrained in the active site of the thioredoxin A (TrxA) gene. The screen selected 88 TrxA peptides that also bind to the full-length TGMV AL1 protein. Plant expression cassettes corresponding to the TrxA peptides and a TGMV A replicon encoding AL1 were cotransfected into tobacco protoplasts, and viral DNA replication was monitored by semiquantitative PCR. In these assays, 31 TrxA peptides negatively impacted TGMV DNA accumulation, reducing viral DNA levels to 13 to 64% of those of the wild type. All of the interfering aptamers also bound to the AL1 protein of cabbage leaf curl virus. A comparison of the 20-mer peptides revealed that their sequences are not random. The alignments detected seven potential binding motifs, five of which are more highly represented among the interfering peptides. One motif was present in 18 peptides, suggesting that these peptides interact with a hot spot in the AL1 N terminus. The peptide aptamers characterized in these studies represent new tools for studying AL1 function and can serve as the basis for the development of crops with broad-based resistance to single-stranded DNA viruses.

Aptamers, Peptide↗

Denaturation and renaturation of viral ribonucleic acd. II. Characterization of the products resulting from annealing R17 ribonucleic acid with denatured replicative form or with denatured replicative intermediate.

The ribonucleic acid (RNA) product resulting from annealing R17 RNA with denatured replicative form or replicative intermediate could be divided into two distinct types of RNA by precipitation in 1.5 m NaCl. The RNA found in the salt supernatant fluid was resistant to digestion by ribonuclease, had a sedimentation coefficient of 15S, and displayed a sharp thermal transition. The RNA in the salt supernatant fluid appeared to be identical to replicative form. The RNA found in the salt precipitate was resistant to digestion by ribonuclease, but possessed both single- and double-stranded characteristics. The RNA sedimented as a broad band in a sucrose gradient, with a sedimentation coefficient of 15S, and displayed a melting transition characteristic of a mixture of single- and double-stranded RNA. Mild ribonuclease digestion of the salt-precipitable RNA produced a ribonuclease-resistant material with sedimentation properties identical to the RNA found in the salt supernatant fluid.

Centrifugation, Density Gradient↗

Host cell participation in small virus replication. I. Replication of M-13 in a strain of Escherichia coli with a temperature-sensitive lesion in deoxyribonucleic acid synthesis.

The replication of M-13 in a strain of Escherichia coli with a thermosensitive lesion in deoxyribonucleic acid synthesis was studied. M-13 failed to replicate at the restrictive temperature, even when the parental replicative form was allowed to form at the permissive temperature. When cells which were actively producing phage at the permissive temperature were shifted to the restrictive temperature, phage production continued. The incorporation of radioactive label into phage particles at 42 C indicated that continued single-strand synthesis was unaffected by the lesion in the host cell.

Chloramphenicol↗

Host cell DNA chain initiation protein requirements for replication of bacteriophage G4 replicative-form DNA.

Bacteriophages G4ev1 and G4bs1 are simple temperature-resistant derivatives of wild-type G4 as demonstrated by restriction endonuclease analyses. The rate of replication of the duplex replicative-form DNA of these phages was normal in dnaB and dnaC mutants of the host, whereas the rate was markedly reduced in a dnaG host mutant at the restrictive temperature. We conclude that G4 duplex DNA replication requires the host cell dnaG protein, but not the dnaB and dnaC proteins. The reasons for the differences between our conclusions and those based on previously published data are documented and discussed.

Bacterial Proteins↗

The vif gene is essential for efficient replication of caprine arthritis encephalitis virus in goat synovial membrane cells and affects the late steps of the virus replication cycle.

Complex retrovirus genomes contain a variable number of accessory genes, among which is the vif gene. We investigated in vitro the role of the vif gene of caprine arthritis encephalitis virus (CAEV) by studying the phenotype of five vif mutants after infection of primary goat synovial membrane (GSM) cells and blood-derived monocytes/macrophages. Any deletion introduced into the vif gene resulted in slow and low viral replication and production of virions with an infectious titer lower than that of wild-type viral particles. The wild-type phenotype could be restored by the trans expression of the vif gene in a complementation assay. Quantitative PCR and reverse transcription-PCR analyses were performed in order to determine which stage of the replicative cycle was impaired by the vif deletion. Our results demonstrated that CAEV Vif did not act at the level of reverse transcription or transcription but rather at the late stage of virus formation and/or release, as lower amounts of virus were produced after a single replicative cycle. The vif-deleted CAEV produced after 24 h of infection was still able to infect GSM cells, indicating that the vif gene is not essential for virus infectivity but is required for efficient virus production.

Amino Acid Sequence↗

Conundrum of the lack of defective RNAs (dRNAs) associated with tobamovirus Infections: dRNAs that can move are not replicated by the wild-type virus; dRNAs that are replicated by the wild-type virus do not move.

Two classes of artificially constructed defective RNAs (dRNAs) of Tobacco mosaic virus (TMV) were examined in planta with helper viruses that expressed one (183 kDa) or both (126 and 183 kDa) of the replicase-associated proteins. The first class of artificially constructed dRNAs had the helicase and polymerase (POL) domains deleted; the second had an intact 126-kDa protein open reading frame (ORF). Despite extremely high levels of replication in protoplasts, the first class of dRNAs did not accumulate in plants. The dRNAs with an intact 126-kDa protein ORF were replicated at moderate levels in protoplasts and in planta when supported by a TMV mutant that expressed the 183-kDa protein but not the 126-kDa protein (183F). These dRNAs were not supported by helper viruses expressing both replicase-associated proteins. De novo dRNAs were generated in plants infected by 183F but not in plants infected with virus with the wild-type replicase. These novel dRNAs each contained a new stop codon near the location of the wild-type stop codon for the 126-kDa protein and had most of the POL domain deleted. The fact that only dRNAs that contained a complete 126-kDa protein ORF moved systemically suggests that expression of a functional 126-kDa protein or the presence of certain sequences and/or structures within this ORF is required for movement of dRNAs. At least two factors may contribute to the lack of naturally occurring dRNAs in association with wild-type TMV infections: an inability of TMV to support dRNAs that can move in plants and the inability of dRNAs that can be replicated by TMV to move in plants.

Defective Viruses↗

Murine coronavirus replication-induced p38 mitogen-activated protein kinase activation promotes interleukin-6 production and virus replication in cultured cells.

Analyses of mitogen-activated protein kinases (MAPKs) in a mouse hepatitis virus (MHV)-infected macrophage-derived J774.1 cell line showed activation of two MAPKs, p38 MAPK and c-Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase (ERK). Activation of MAPKs was evident by 6 h postinfection. However, UV-irradiated MHV failed to activate MAPKs, which demonstrated that MHV replication was necessary for their activation. Several other MHV-permissive cell lines also showed activation of both p38 MAPK and JNK, which indicated that the MHV-induced stress-kinase activation was not restricted to any particular cell type. The upstream kinase responsible for activating MHV-induced p38 MAPK was the MAPK kinase 3. Experiments with a specific inhibitor of p38 MAPK, SB 203580, demonstrated that MHV-induced p38 MAPK activation resulted in the accumulation of interleukin-6 (IL-6) mRNAs and an increase in the production of IL-6, regardless of MHV-induced general host protein synthesis inhibition. Furthermore, MHV production was suppressed in SB 203580-treated cells, demonstrating that activated p38 MAPK played a role in MHV replication. The reduced MHV production in SB 203580-treated cells was, at least in part, due to a decrease in virus-specific protein synthesis and virus-specific mRNA accumulation. Interestingly, there was a transient increase in the amount of phosphorylation of the translation initiation factor 4E (eIF4E) in infected cells, and this eIF4E phosphorylation was p38 MAPK dependent; it is known that phosphorylated eIF4E enhances translation rates of cap-containing mRNAs. Furthermore, the upstream kinase responsible for eIF4E phosphorylation, MAPK-interacting kinase 1, was also phosphorylated and activated in response to MHV infection. Our data suggested that host cells, in response to MHV replication, activated p38 MAPK, which subsequently phosphorylated eIF4E to efficiently translate certain host proteins, including IL-6, during virus-induced severe host protein synthesis inhibition. MHV utilized this p38 MAPK-dependent increase in eIF4E phosphorylation to promote virus-specific protein synthesis and subsequent progeny virus production. Enhancement of virus-specific protein synthesis through virus-induced eIF4E activation has not been reported in any other viruses.

Animals↗

Assessment of the role of the central DNA flap in human immunodeficiency virus type 1 replication by using a single-cycle replication system.

In this study, reverse transcriptase (RT)- and integrase (IN)-defective human immunodeficiency virus type 1 (HIV-1) was transcomplemented with Vpr-RT-IN fusion proteins to delineate pol sequences important for HIV-1 replication. Our results reveal that a 194-bp sequence encompassing the 3'end of the IN gene and containing the central DNA flap is necessary and sufficient for efficient HIV-1 single-cycle replication in dividing and nondividing cells. Furthermore, we show that the central DNA flap enhances HIV-1 single-round replication by five- to sevenfold, primarily by facilitating nuclear import of proviral DNA. In agreement with previous reports, our data support a functional role of the central DNA flap during the early stages of HIV-1 infection.

Cell Nucleus↗

Human T-cell leukemia virus type 1 expressing nonoverlapping tax and rex genes replicates and immortalizes primary human T lymphocytes but fails to replicate and persist in vivo.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus associated primarily with adult T-cell leukemia and neurological disease. HTLV-1 encodes the positive trans-regulatory proteins Tax and Rex, both of which are essential for viral replication. Tax activates transcription initiation from the viral long terminal repeat and modulates the transcription or activity of a number of cellular genes. Rex regulates gene expression posttranscriptionally by facilitating the cytoplasmic expression of incompletely spliced viral mRNAs. Tax and Rex mutants have been identified that have defective activities or impaired biochemical properties associated with their function. To ultimately determine the contribution of specific protein activities on viral replication and cellular transformation of primary T cells, mutants need to be characterized in the context of an infectious molecular clone. Since the tax and rex genes are in partially overlapping reading frames, mutation in one gene frequently disrupts the other, confounding interpretation of mutational analyses in the context of the virus. Here we generated and characterized a unique proviral clone (H1IT) in which the tax and rex genes were separated by expressing Tax from an internal ribosome entry site. We showed that H1IT expresses both functional Tax and Rex. In short- and long-term coculture assays, H1IT was competent to infect and immortalize primary human T cells similar to wild-type HTLV-1. In contrast, H1IT failed to efficiently replicate and persist in inoculated rabbits, thus emphasizing the importance of temporal and quantitative regulation of specific mRNA for viral survival in vivo.

Cell Transformation, Viral↗

Role of multifunctional autonomously replicating sequence binding factor 1 in the initiation of DNA replication and transcriptional control in Saccharomyces cerevisiae.

Autonomously replicating sequence (ARS) binding factor 1 (ABF1) is an abundant DNA-binding protein that specifically recognizes the motif RTCRYN5ACG at many sites in the yeast genome, including promoter elements, mating-type silencers, and ARSs. Mutational analysis of these sites suggests that ABF1 is involved in constitutive and carbon source-regulated transcriptional activation, transcriptional silencing, and ARS activity. To better assess the role of ABF1 in DNA replication and transcriptional control, temperature-sensitive lethal mutations in the ABF1 gene were isolated. Several of the abf1(Ts) strains show rapid growth arrest at the nonpermissive temperature. At the semipermissive temperature, these strains show an ARS-specific defect in the mitotic stability of ARS-CEN plasmids, such that the abf1 mutants show defects in ARS function identical to those of mutants bearing the mutations in the cis-acting ABF1 binding sites analyzed previously by numerous investigators. Flow cytometric analysis and in vivo DNA labeling experiments on an alpha-factor synchronized abf1(Ts) strain showed that at the nonpermissive temperature, these cells fail to progress efficiently from G1 through S phase and synthesize DNA at 25% of the level seen in the isogenic ABF1 strain. RNA synthesis is also reduced in the abf1(Ts) strains. In addition, transcriptional activation by an ABF1 binding site upstream activation sequence is completely defective in an abf1(Ts) strain at the semipermissive temperature. These phenotypes provide evidence that the same protein, ABF1, functions in the initiation of DNA replication and transcriptional activation.

Alleles↗

Identification of a multifunctional domain in autonomously replicating sequence-binding factor 1 required for transcriptional activation, DNA replication, and gene silencing.

Autonomously replicating sequence-binding factor 1 (ABF1) is a multifunctional, site-specific DNA binding protein that is essential for cell viability in Saccharomyces cerevisiae. ABF1 plays a direct role in transcriptional activation, stimulation of DNA replication, and gene silencing at the mating-type loci. Here we demonstrate that all three activities of ABF1 are conferred by the C terminus of the protein (amino acids [aa] 604 to 731). Furthermore, a detailed mutational analysis has revealed two important clusters of amino acid residues in the C terminus (C-terminal sequence 1 [CS1], aa 624 to 628; and CS2, aa 639 to 662). While both regions play a pivotal role in supporting cell viability, they make distinct contributions to ABF1 functions in various nuclear processes. CS1 specifically participates in transcriptional silencing and/or repression in a context-dependent manner, whereas CS2 is universally required for all three functions of ABF1. When tethered to specific regions of the genome, a 30-aa fragment that contains CS2 alone is sufficient for activation of transcription and chromosomal replication. In addition, CS2 is responsible for ABF1-mediated chromatin remodeling. Based on these results, we suggest that ABF1 may function as a chromatin-reorganizing factor to increase accessibility of the local chromatin structure, which in turn facilitates the action of additional factors to establish either an active or repressed chromatin state.

Amino Acid Sequence↗

The replication fork barrier site forms a unique structure with Fob1p and inhibits the replication fork.

The replication fork barrier site (RFB) is an approximately 100-bp DNA sequence located near the 3' end of the rRNA genes in the yeast Saccharomyces cerevisiae. The gene FOB1 is required for this RFB activity. FOB1 is also necessary for recombination in the ribosomal DNA (rDNA), including increase and decrease of rDNA repeat copy number, production of extrachromosomal rDNA circles, and possibly homogenization of the repeats. Despite the central role that Foblp plays in both replication fork blocking and rDNA recombination, the molecular mechanism by which Fob1p mediates these activities has not been determined. Here, I show by using chromatin immunoprecipitation, gel shift, footprinting, and atomic force microscopy assays that Fob1p directly binds to the RFB. Fob1p binds to two separated sequences in the RFB. A predicted zinc finger motif in Fob1p was shown to be essential for the RFB binding, replication fork blocking, and rDNA recombination activities. The RFB seems to wrap around Fob1p, and this wrapping structure may be important for function in the rDNA repeats.

Base Sequence↗

Conversion of dengue virus replicative form RNA (RF) to replicative intermediate (RI) by nonstructural proteins NS-5 and NS-3.

Dengue viruses infect more than 100 million people each year and cause serious clinical manifestations. It is important to understand the replication of these viruses so that therapeutic and/or prophylactic agents may be designed. Dengue virus type 2 nonstructural proteins NS-5 and NS-3 were produced by in vitro transcription and translation of cloned genes. Both proteins possessed RNA-dependent RNA polymerase activity as measured by their ability to convert purified replicative form (RF) RNA to replicative intermediate (RI). The recombinant proteins, however, required one or more cellular protein(s) for their activity. Examination of NS-3 protein sequence revealed heretofore unnoticed sequence similarities with other polymerases.

Amino Acid Sequence↗

Polyanionic (i.e., polysulfonate) dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps (reverse transcriptase/integrase) in the virus replicative cycle.

Polyanionic dendrimers were synthesized and evaluated for their antiviral effects. Phenyldicarboxylic acid (BRI6195) and naphthyldisulfonic acid (BRI2923) dendrimers were found to inhibit the replication of human immunodeficiency virus type 1 (HIV-1; strain III(B)) in MT-4 cells at a EC(50) of 0.1 and 0.3 microg/ml, respectively. The dendrimers were not toxic to MT-4 cells up to the highest concentrations tested (250 microg/ml). These compounds were also effective against various other HIV-1 strains, including clinical isolates, HIV-2 strains, simian immunodeficiency virus (SIV, strain MAC(251)), and HIV-1 strains that were resistant to reverse transcriptase inhibitors. HIV strains containing mutations in the envelope glycoprotein gp120 (engendering resistance to known adsorption inhibitors) displayed reduced sensitivity to the dendrimers. The compounds inhibited the binding of wild-type virus and recombinant virus (containing wild-type gp120) to MT-4 cells at concentrations comparable to those that inhibited the replication of HIV-1(III(B)) in these cells. Cellular uptake studies indicated that BRI2923, but not BRI6195, permeates into MT-4 and CEM cells. Accordingly, the naphtyldisulfonic acid dendrimer (BRI2923) proved able to inhibit later steps of the replication cycle of HIV, i.e., reverse transcriptase and integrase. NL4.3 strains resistant to BRI2923 were selected after passage of the virus in the presence of increasing concentrations of BRI2923. The virus mutants showed 15-fold reduced sensitivity to BRI2923 and cross-resistance to known adsorption inhibitors. However, these virus mutants were not cross-resistant to reverse transcriptase inhibitors or protease inhibitors. We identified several mutations in the envelope glycoprotein gp120 gene (i.e., V2, V3, and C3, V4, and C4 regions) of the BRI2923-resistant NL4.3 strains that were not present in the wild-type NL4.3 strain, whereas no mutations were found in the reverse transcriptase or integrase genes.

Animals↗

Specialized nucleoprotein structures at the origin of replication of bacteriophage lambda. Protein association and disassociation reactions responsible for localized initiation of replication.

Binding of the O protein of phage lambda to the replication origin (ori lambda) results in the formation of an organized nucleoprotein structure termed the O-some. The O-some serves to localize and initiate a six-protein sequential reaction that provides for localized unwinding of the origin region, the critical prepriming step for precise initiation of DNA replication. By the use of electron microscopy of gold-tagged antibody complexes, we have defined four stages of protein association and dissociation reactions that are involved in the prepriming pathway. First, as defined previously, O protein binds to multiple DNA sites and self-associates to form the O-some. Second, lambda P and host DnaB proteins add to the O-some to generate an O.P.DnaB.ori lambda complex. Addition of the DnaK and DnaJ proteins yields a third stage complex containing DnaK, DnaJ, O, P, and DnaB. With the addition of ATP and single-strand binding protein (SSB), the P protein is largely removed, and the DnaB acts as a helicase to generate locally unwound, SSB-coated single strand DNA. Thus, the initiation of lambda DNA replication requires ordered assembly and partial disassembly of specialized nucleoprotein structures. The disassembly activity of DnaK and DnaJ may be their general role in the heat shock response.

Bacteriophage lambda↗

[Organization of mammalian genome replication: data on the high rate of DNA replication in replicons of structural heterochromatin].

By the autoradiography, the increase of the mean rate of replication fork movement in DNA was shown for human skin fibroblasts during S-period induced by reseeding the stationary culture; the portion of high-rate replicons growing parallel to the increase in numbers of cells, in which the constitutive heterochromatin was replicating. Furthermore, the heterogeneity of replicons was investigated in regard to the rate of DNA chain growth in asynchronous cell populations of human and three rodent species (Microtus agrestis, Tscherskia triton, Cricetulus griseus). A positive correlation was found between the portion of replicons, with a relatively high rate of replication (more than 60 micron/h), and the relative amounts of C-heterochromatin in genomes of these species. On the basis of these studies it has been assumed, that the replicons with the high rate of DNA chain growth belong to the constitutive heterochromatin.

Animals↗

DNA replication in Physarum polycephalum. Analysis of replicating nuclear DNA using the electron microscope.

DNA has been isolated from Physarum polycephalum nuclei obtained from macroplasmodia at different stages in the mitotic cycle, and examined using the electron microscope. Putative replicating structures were identified, the majority of which contained clusters of 2--37 'microbubbles', each microbubble corresponding to a segment of DNA 100--5000 nucleotides long. The microbubble-containing structures are unstable in the formamide hyperphase used to prepare specimens for electron microscopy, possibly due to dissociation of newly replicated nascent DNA fragments from the parental DNA template during manipulation. The microbubble clusters present in early S-phase DNA extent over segments averaging 16400 nucleotide residues, and are separated by non-replicated regions of DNA varying in length from 10000 to 50000 nucleotides. It is suggested that each microbubble cluster may represent a 'replicon', and that many 'replicons' in Physarum DNA may contain several sites for the initiation of DNA synthesis that are active during S-phase.

Cell Nucleus↗

Transformation of naturally competent Streptococcus mutans with replicative and non-replicative Tn916-containing plasmids: implications for a mechanism of transposition.

Based on the observations reported here and what is known concerning transformation of naturally competent strains of S. mutans and other streptococcal species such as S. gordonii, we propose the model shown in Figure 2. The Tn916-intermediate transforms S. mutans as originally proposed for B. subtilis by Scott and coworkers [8]. It is not clear in either system (B. subtilis or S. mutans) whether the Tn916 intermediate enters the cell as ds-DNA or ss-DNA. Because it is likely that transformation of B. subtilis via formation of protoplasts involves a mechanism quite different from natural transformation in S. mutans, it would be unwise to extrapolate findings from their studies. If Tn916 enters S. mutans in a manner similar to plasmid or chromosomal DNA, we would assume that Tn916 binds to a cell receptor and as one strand enters, the other is degraded [9]. This leaves open the question of whether Tn916 recircularizes as ds-DNA before it inserts into the chromosome or whether it remains as ss-DNA, if, indeed, it enters as ss-DNA. The transformation efficiency for the Tn916 intermediate (approximately 10(-7) precluded kinetics studies such as those performed with pAM118. Poyart-Salmeron and coworkers [11] however, described a model in which Tn1545 inserts into the target site as a ds-DNA circular molecule, similar to that seen with lambda phage. Perhaps the most interesting finding presented here is that the predominant mechanism of insertion of Tn916 into the chromosome of the recipient occurs after Tn916 enters the cell. The replicative plasmid pAM118 evidently forms by two-hit kinetics followed by intracellular excision and transposition of Tn916. The helper-rescue experiment shows that in this system, the formation of Tcr transformants, and hence the integration of Tn916, was a function of the transformation efficacy of plasmid pAM118. Since intracellular excision of Tn916 probably follows the re-formation of the plasmid pAM118, the rate-limiting step in this system would be the formation of the transient, intracellular plasmid pAM118. (The transient white colony phenotype probably denotes the slower growth rate of transformants that acquire the large replicative plasmid pAM118). Our findings demonstrate that a practical way of promoting Tn916 insertions into chromosomal DNA for the purpose of obtaining mutations is to use a helper-rescue system. Our model supports the concept that the majority of Tn916 inserts arise from a mechanism similar to 'zygotic induction' as proposed for S. sanguis (gordonii) [1]. However, the frequencies for the co-establishment of the replicative plasmid (Emr) and Tn916 inserts (Tcr) in their paper (10(-6)) differ from our observations for S. mutans. We found nearly 100% of Tcr white colonies to be Emr whereas in S. gordonii, only a fraction (approximately 1%) exhibited the TcrEmr phenotype. If both phenotypes arose independently, the frequency of the TcrEmr phenotype would be 10(-8) rather than 10(-6) survivors/recipients as observed. It was surmised that both Tcr and Emr transformants arise dependently [1] where both the Tn916 intermediate and pAM118 contribute to the formation of Tn916 inserts. We conclude from their data, however, that most Tcr arose from the Tn916-intermediate formed in the donor, in agreement with the explanation of these data by Scott [12]. Support for the contention that the Tcr arose in S. gordonii from transformation by the Tn916-intermediate as in S. mutans (yellows), and not from intracellular excision from pAM118, comes from the observation that so few Tcr are Ems and because pAM150 (rep-) yields Tcr at the same frequency as the rep+ pAM118 in their experiments. In summary, the Tn916 intermediate is capable of transforming S. mutans. In contrast to the hypothesis of Scott [12], however, the Tn916 intermediate is not the only form involved in the transformat++t

Chromosomes, Bacterial↗