Delineation of regulatory domains of early (beta) and late (gamma 2) genes by construction of chimeric genes expressed in herpes simplex virus 1 genomes.

Mavromara-Nazos, Penelope; Roizman, Bernard

doi:10.1073/pnas.86.11.4071

Cited by 37 publications

(38 citation statements)

References 32 publications

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“…Fifth, the ICP8 recombinase activity could lead to conformational changes in viral progeny DNA that allow efficient late gene transcription. cis-acting changes in viral genomes following viral DNA replication are known to activate late gene transcription (26). ICP8 is known to bind to viral progeny DNA (23), and the recombinase activity of ICP8 could act to resolve concatemers and increase viral late gene transcription.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Divalent Metal Cation Binding Site in Herpes Simplex Virus 1 (HSV-1) ICP8 Required for HSV Replication

Bryant

Yan

Dreyfus

et al. 2012

J Virol

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Herpes simplex virus 1 (HSV-1) ICP8 is a single-stranded DNA-binding protein that is necessary for viral DNA replication and exhibits recombinase activity in vitro . Alignment of the HSV-1 ICP8 amino acid sequence with ICP8 homologs from other herpesviruses revealed conserved aspartic acid (D) and glutamic acid (E) residues. Amino acid residue D1087 was conserved in every ICP8 homolog analyzed, indicating that it is likely critical for ICP8 function. We took a genetic approach to investigate the functions of the conserved ICP8 D and E residues in HSV-1 replication. The E1086A D1087A mutant form of ICP8 failed to support the replication of an ICP8 mutant virus in a complementation assay. E1086A D1087A mutant ICP8 bound DNA, albeit with reduced affinity, demonstrating that the protein is not globally misfolded. This mutant form of ICP8 was also recognized by a conformation-specific antibody, further indicating that its overall structure was intact. A recombinant virus expressing E1086A D1087A mutant ICP8 was defective in viral replication, viral DNA synthesis, and late gene expression in Vero cells. A class of enzymes called DDE recombinases utilize conserved D and E residues to coordinate divalent metal cations in their active sites. We investigated whether the conserved D and E residues in ICP8 were also required for binding metal cations and found that the E1086A D1087A mutant form of ICP8 exhibited altered divalent metal binding in an in vitro iron-induced cleavage assay. These results identify a novel divalent metal cation-binding site in ICP8 that is required for ICP8 functions during viral replication.

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Section: Discussionmentioning

confidence: 99%

Identification of a Divalent Metal Cation Binding Site in Herpes Simplex Virus 1 (HSV-1) ICP8 Required for HSV Replication

Bryant

Yan

Dreyfus

et al. 2012

J Virol

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“…While early viral gene promoters typically consists of distal regulatory sequences upstream of the TATA box, the critical elements of late promoters have been mapped to regions near the transcription start sites (8,10,12,13,16,25,32,36). These cis-acting elements include a TATA box (8,12,16), an initiator element at the transcription start site (32,36), and a downstream activation sequence in the 5Ј-untranslated region (10,13,25). Multiple HSV proteins (ICP4, ICP8, and ICP27) have been shown to be necessary for efficient expression of late genes (9,20,28).…”

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confidence: 99%

ORF30 and ORF34 Are Essential for Expression of Late Genes in Murine Gammaherpesvirus 68

Park²,

Kim³

et al. 2009

J Virol

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A hallmark of productive infection by DNA viruses is the coupling of viral late gene expression to genome replication. Here we report the identification of open reading frame 30 (ORF30) and ORF34 as viral trans factors crucial for activating late gene transcription following viral DNA replication during lytic infection of murine gammaherpesvirus 68 (MHV-68). The mutant virus lacking either ORF30 or ORF34 underwent normal DNA replication but failed to express viral late gene transcripts, leading to nonproductive infection. In a reporter assay system, ORF30 and ORF34 were required for MHV-68 to activate the viral late gene promoters. Furthermore, studies using chromatin immunoprecipitation assays showed that the recruitment of RNA polymerase II to the viral late promoters during lytic infection was significantly reduced in the absence of ORF30 or ORF34. Together, the results suggest that ORF30 and ORF34 may play an important role in the assembly of the transcription initiation complex at the late gene promoters. Our discovery of the viral mutants that uncouple late gene transcription from DNA replication lays an important foundation to dissect the mechanism of this critical step of gene expression regulation.

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“…We are faced, however with enormous gaps. Although promoter substitutions revealed that the sequences conferring γ 2 specificity resides in the 5’ transcribed noncoding domain downstream of the TATA box (Mavromara et al, 1989), we have no cohesive pictures for the differential expression of β and γ 2 genes.…”

Section: Productive Infection At the Portal Of Entrymentioning

confidence: 78%

The 3 facets of regulation of herpes simplex virus gene expression: A critical inquiry

Roizman

Zhou

2015

Virology

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On entry into the body herpes simplex viruses (HSV) replicate in a series of steps that involves derepression of viral DNA activated by VP16, a virion protein, and sequential transcription of viral genes in a cascade fashion. HSV also enters into neurons in which viral DNA maintained as heterochromatin and with few exceptions viral gene expression is silenced. A third face of the interaction of HSV with its host cells takes place at the moment when the silenced viral genome in neurons is abruptly derepressed. The available data do no reveal evidence that HSV encodes different regulatory programs for each facet of its interaction with its host cells. Rather the data point to significant gaps in our knowledge of the mechanisms by which each facet is initiated and the roles of the infected cells at each facet of the interaction of viral gene products with the host cell.

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Delineation of regulatory domains of early (beta) and late (gamma 2) genes by construction of chimeric genes expressed in herpes simplex virus 1 genomes.

Cited by 37 publications

References 32 publications

Identification of a Divalent Metal Cation Binding Site in Herpes Simplex Virus 1 (HSV-1) ICP8 Required for HSV Replication

Identification of a Divalent Metal Cation Binding Site in Herpes Simplex Virus 1 (HSV-1) ICP8 Required for HSV Replication

ORF30 and ORF34 Are Essential for Expression of Late Genes in Murine Gammaherpesvirus 68

The 3 facets of regulation of herpes simplex virus gene expression: A critical inquiry

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