Aberrant RNA polymerase Initiation and Processivity on the Genome of a Herpes Simplex Virus 1 Mutant Lacking ICP27
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ABSTRACT:
PROVIDER: PRJNA1013976 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25943782.fastq.gz | Fastqsanger.gz | |||
| SRR25943783.fastq.gz | Fastqsanger.gz | |||
| SRR25943784.fastq.gz | Fastqsanger.gz | |||
| SRR25943785.fastq.gz | Fastqsanger.gz | |||
| SRR25943786.fastq.gz | Fastqsanger.gz |
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Project description:Within the first 15 minutes of infection, herpes simplex virus 1 (HSV-1) immediate early proteins repurpose cellular RNA polymerase (Pol II) for viral transcription. An important role of the viral infected cell protein 27 (ICP27) is to facilitate viral pre-mRNA processing and export of viral mRNA to the cytoplasm. Here, we use precision nuclear run-on followed by deep sequencing (PRO-seq) to characterize transcription of a viral ICP27 null mutant. At 1.5 and 3 hours post infection (hpi) we observed Increased total levels of Pol II on the mutant viral genome and accumulation of Pol II downstream of poly A sites indicating increased levels of initiation and processivity. By 6 hpi Pol II accumulation on specific mutant viral genes was higher than wt virus either at or upstream of poly A signals, depending on the gene. The PRO-seq profile of the ICP27 mutant on late genes at 6 hpi was similar but not identical to that caused by treatment with flavopiridol, a known inhibitor of RNA processivity. This pattern was different from PRO-seq profiles of other α gene mutants, and upon inhibition of viral DNA replication with PAA. Together, these results indicate that ICP27 contributes to the repression of aberrant viral transcription at 1.5 and 3 hpi by inhibiting initiation and decreasing RNA processivity. However, ICP27 is needed to enhance processivity on most late genes by 6 hpi in a mechanism distinguishable from its role in viral DNA replication.
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Project description:ICP22 of Herpes Simplex Virus 1 decreases RNA Polymerase Processivity
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Project description:These data files consist of Illumina next seq 500 sequencing data from precision nuclear run-on and global nuclear run-on experiments conducted with human epithelial Hep2 cells that have been infected with human herpes simplex virus-1 (F) strain mutants. The results of these studies suggest that ICP22 is necessary for reducing Pol II processivity on the viral genome which results in its maintenance on the viral genome over the course of infection. While human reads continued to decrease over the time course of infection in the repair virus, this did not occur in the ICP22 deletion virus where over time the number of human reads increased over the time course of infection rather than decreasing. The effects of ICP22 deletion were separable from inhibiting HSV-1 DNA replication to the extent that ICP22 deletion resulted in a decrease in Pol levels only at 6 hpi and not at 3 hpi as was observed in the mutant
2022-01-05 | GSE169574 | GEO
Project description:Within the first 15 minutes of infection, herpes simplex virus 1 immediate early proteins repurpose cellular RNA polymerase (Pol II) for viral transcription. An important role of the viral-infected cell protein 27 (ICP27) is to facilitate viral pre-mRNA processing and export viral mRNA to the cytoplasm. Here, we use precision nuclear run-on followed by deep sequencing (PRO-seq) to characterize transcription of a viral ICP27 null mutant. At 1.5 and 3 hours post infection (hpi), we observed increased total levels of Pol II on the mutant viral genome and accumulation of Pol II downstream of poly A sites indicating increased levels of initiation and processivity. By 6 hpi, Pol II accumulation on specific mutant viral genes was higher than that on wild-type virus either at or upstream of poly A signals, depending on the gene. The PRO-seq profile of the ICP27 mutant on late genes at 6 hpi was similar but not identical to that caused by treatment with flavopiridol, a known inhibitor of RNA processivity. This pattern was different from PRO-seq profiles of other α gene mutants and upon inhibition of viral DNA replication with PAA. Together, these results indicate that ICP27 contributes to the repression of aberrant viral transcription at 1.5 and 3 hpi by inhibiting initiation and decreasing RNA processivity. However, ICP27 is needed to enhance processivity on most late genes by 6 hpi in a mechanism distinguishable from its role in viral DNA replication.IMPORTANCEWe developed and validated the use of a processivity index for precision nuclear run-on followed by deep sequencing data. The processivity index calculations confirm infected cell protein 27 (ICP27) induces downstream of transcription termination on certain host genes. The processivity indices and whole gene probe data implicate ICP27 in transient immediate early gene-mediated repression, a process that also requires ICP4, ICP22, and ICP0. The data indicate that ICP27 directly or indirectly regulates RNA polymerase (Pol II) initiation and processivity on specific genes at specific times post infection. These observations support specific and varied roles for ICP27 in regulating Pol II activity on viral genes in addition to its known roles in post transcriptional mRNA processing and export.
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Project description:Herpes simplex virus mutants lacking the vhs gene are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties vhs-deleted virus have been proposed as live-attenuated viruses. Despite these findings and their implications for vacccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficent viruses replicate to reduced levels in interferon(IFN)- primed cells. Furthermore, vhs-defective viruses induce increased levels of IFNβ and IFNβ-stimulated genes, and increased levels of eIF2α phosphorylation in infected cells. In addition, we demonstrate a generalized over-expression of viral RNAs following infection with a vhs-deficient virus. This suggests increased expression of IFN pathway inducing double stranded RNA, a potent pathogen-associated molecular pattern (PAMP). Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as critical determinant of viral pathogenesis. Keywords: time course, genetic modification
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