Herpes simplex virus induces a processing factor that stimulates poly(A) site usage

McLauchlan, John; Simpson, Scott; Jb, Clements

doi:10.1016/0092-8674(89)90765-4

Cited by 76 publications

(80 citation statements)

References 60 publications

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“…A clue to the mechanism of ICP27 action was provided by Sandri-Goldin and Mendoza (53), who showed that ICP27 enhances expression of constructs bearing a synthetic and incomplete polyadenylation signal and inhibits expression of reporter genes bearing certain introns in transient-cotransfection assays. A complementary series of studies by Clements and colleagues demonstrated that HSV infection alters the specificity of the host polyadenylation machinery in an ICP27-dependent fashion, thereby allowing more efficient use of a subset of viral polyadenylation signals (31)(32)(33). These findings indicate that ICP27 modulates intranuclear processing of pre-mRNAs and suggest that it inhibits splicing of at least some intron-bearing transcripts (53).…”

Section: Herpes Simplex Virus (Hsv) Is a Large Enveloped Dna Virus Thmentioning

confidence: 98%

Herpes Simplex Virus ICP27 Induces Cytoplasmic Accumulation of Unspliced Polyadenylated α-Globin Pre-mRNA in Infected HeLa Cells

Cheung¹,

Ellison

Verity

et al. 2000

J Virol

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Transcripts of most intron-bearing cellular genes must be processed by the splicing machinery in order to efficiently accumulate and gain access to the cytoplasm. However, we found that herpes simplex virus induces cytoplasmic accumulation of both spliced and unspliced polyadenylated ␣-globin RNAs in infected HeLa cells. Accumulation of the unspliced RNA required the immediate-early protein ICP27, and ICP27 was sufficient (in combination with ICP4) to produce this effect in a transient-transfection assay. However, expression of ICP27 did not markedly alter the levels of fully spliced ␣-globin transcripts in infected cells. These data demonstrate that the previously documented effects of ICP27 on the cellular splicing apparatus do not greatly inhibit splicing of ␣-globin RNA and argue that ICP27 induces a splicing-independent pathway for ␣-globin RNA accumulation and nuclear export. [L]) are sequentially activated in a regulatory cascade driven by viral gene products, while expression of most host cell genes is strongly suppressed. The HSV lytic program is initiated by the virion transactivator VP16, which acts in combination with host factors to stimulate transcription of the five IE genes (reviewed in references 16 and 60). Four of the IE proteins (ICP0, ICP4, ICP22, and ICP27) then play key roles in orchestrating expression of the viral E and L genes (10,30,48,49,55,59,63).Early studies demonstrated that the HSV lytic cascade involves both transcriptional and posttranscriptional controls of mRNA metabolism (64). Mounting evidence suggests that the immediate-early (IE) protein ICP27 contributes to the posttranscriptional component of the viral regulatory program (57; reviewed in reference 51). ICP27 is an essential regulator that stimulates accumulation of a subset of viral E and L mRNAs and is required for efficient viral DNA replication (12,30,34,43,44,48,56,62). A clue to the mechanism of ICP27 action was provided by Sandri-Goldin and Mendoza (53), who showed that ICP27 enhances expression of constructs bearing a synthetic and incomplete polyadenylation signal and inhibits expression of reporter genes bearing certain introns in transient-cotransfection assays. A complementary series of studies by Clements and colleagues demonstrated that HSV infection alters the specificity of the host polyadenylation machinery in an ICP27-dependent fashion, thereby allowing more efficient use of a subset of viral polyadenylation signals (31-33). These findings indicate that ICP27 modulates intranuclear processing of pre-mRNAs and suggest that it inhibits splicing of at least some intron-bearing transcripts (53).The hypothesis that ICP27 impairs RNA splicing has been supported by a considerable amount of data showing the following: (i) unspliced pre-RNA derived from the intron-bearing HSV genes encoding ICP0 and UL15 accumulate in the nuclei of some cell types infected with wild-type HSV but not with an ICP27 mutant (20,21,40), (ii) ICP27 colocalizes with and redistributes snRNPs in HSV-infected cell nuclei (38), (iii) ICP2...

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Section: Herpes Simplex Virus (Hsv) Is a Large Enveloped Dna Virus Thmentioning

confidence: 98%

Herpes Simplex Virus ICP27 Induces Cytoplasmic Accumulation of Unspliced Polyadenylated α-Globin Pre-mRNA in Infected HeLa Cells

Cheung¹,

Ellison

Verity

et al. 2000

J Virol

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“…ICP27 is the other essential regulatory IE gene (51), encoding a nuclear phosphoprotein which performs a number of diverse functions. These include repression of IE genes, control of the switch between E and L gene expression, and selection of transcriptional termination sites (40,42). ICP27 normally mediates the shutoff of host protein synthesis by sequestering snRNPs (23,24).…”

Section: Discussionmentioning

confidence: 99%

Multiple Immediate-Early Gene-Deficient Herpes Simplex Virus Vectors Allowing Efficient Gene Delivery to Neurons in Culture and Widespread Gene Delivery to the Central Nervous System In Vivo

Lilley¹,

Groutsi²,

Han³

et al. 2001

J Virol

112

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Herpes simplex virus (HSV) has several potential advantages as a vector for delivering genes to the nervous system. The virus naturally infects and remains latent in neurons and has evolved the ability of highly efficient retrograde transport from the site of infection at the periphery to the site of latency in the spinal ganglia. HSV is a large virus, potentially allowing the insertion of multiple or very large transgenes. Furthermore, HSV does not integrate into the host chromosome, removing any potential for insertional activation or inactivation of cellular genes. However, the development of HSV vectors for the central nervous system that exploit these properties has been problematical. This has mainly been due to either vector toxicity or an inability to maintain transgene expression. Here we report the development of highly disabled versions of HSV-1 deleted for ICP27, ICP4, and ICP34.5/open reading frame P and with an inactivating mutation in VP16. These viruses express only minimal levels of any of the immediate-early genes in noncomplementing cells. Transgene expression is maintained for extended periods with promoter systems containing elements from the HSV latency-associated transcript promoter (J. A. Palmer et al., J. Virol. 74:5604-5618, 2000). Unlike less-disabled viruses, these vectors allow highly effective gene delivery both to neurons in culture and to the central nervous system in vivo. Gene delivery in vivo is further enhanced by the retrograde transport capabilities of HSV. Here the vector is efficiently transported from the site of inoculation to connected sites within the nervous system. This is demonstrated by gene delivery to both the striatum and substantia nigra following striatal inoculation; to the spinal cord, spinal ganglia, and brainstem following injection into the spinal cord; and to retinal ganglion neurons following injection into the superior colliculus and thalamus.

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“…One possibility is that transcriptional readthrough from the inserted sequences in vFJ7 and vFJl0 could lower the amount of USll mRNA available for translation either by production of anti-sense mRNA or transcriptional interference. Recently, it has been shown that readthrough of the HSV-2 IE5 poly(A) site sequences inserted into the virus vector occurs during lytic infection (McLauchlan et al, 1989). Thus, inefficient processing at the poly(A) sites of the CAT and flgalactosidase genes present in vFJ7 and vFJ10 could produce transcripts complementary to USll mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…In this study we have used different promoters to drive CAT gene expression in vFJ7 and vFJ10, but protein-coding and mRNA 3' processing sequences can also be manipulated. Analysis of a CAT gene cassette, containing tandemly arranged poly(A) sites, inserted into 1802 has already facilitated identification of an HSV-induced factor which alters poly(A) site usage (McLauchlan et al, 1989). It is also relatively easy to construct alternative expression plasmids to use with these vectors.…”

Section: Discussionmentioning

confidence: 99%

Insertion of DNA Sequences at a Unique Restriction Enzyme Site Engineered for Vector Purposes into the Genome of Herpes Simplex Virus Type 1

Rixon¹,

McLauchlan²

1990

Journal of General Virology

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We describe the construction of a novel herpes simplex virus (HSV) vector containing a unique XbaI restriction enzyme cloning site in an intergenic position in the short unique genome region. Sequences can be inserted at this site with high efficiency by ligation with Xbaldigested vector DNA. A series of plasmids has been designed for use with this vector. These allow protein coding sequences to be placed under the control of various transcriptional regulation signals and then isolated as XbaI fragments ready for insertion into the vector. The XbaI fragments also contain the /~-galactosidase gene thereby facilitating selection of recombinant virus by screening for blue plaques. A variant of the vector has been made based on the temperature-sensitive (ts) mutant tsK, which expresses only immediate early (IE) genes at non-permissive temperatures. Chloramphenicol acetyltransferase was used as a reporter gene to assess the fidelity of expression of sequences cloned into this position. Under these circumstances IE and early HSV promoters were shown to behave as expected in both wild-type and ts vectors.

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Herpes simplex virus induces a processing factor that stimulates poly(A) site usage

Cited by 76 publications

References 60 publications

Herpes Simplex Virus ICP27 Induces Cytoplasmic Accumulation of Unspliced Polyadenylated α-Globin Pre-mRNA in Infected HeLa Cells

Herpes Simplex Virus ICP27 Induces Cytoplasmic Accumulation of Unspliced Polyadenylated α-Globin Pre-mRNA in Infected HeLa Cells

Multiple Immediate-Early Gene-Deficient Herpes Simplex Virus Vectors Allowing Efficient Gene Delivery to Neurons in Culture and Widespread Gene Delivery to the Central Nervous System In Vivo

Insertion of DNA Sequences at a Unique Restriction Enzyme Site Engineered for Vector Purposes into the Genome of Herpes Simplex Virus Type 1

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