Abstract
Herpes simplex virus-1 (HSV-1) replicates within the nucleus coopting the host's RNA Polymerase II (Pol II) machinery for production of viral mRNAs culminating in host transcriptional shut off. The mechanism behind this rapid reprogramming of the host transcriptional environment is largely unknown. We identified ICP4 as responsible for preferential recruitment of the Pol II machinery to the viral genome. ICP4 is a viral nucleoprotein which binds double-stranded DNA. We determined ICP4 discriminately binds the viral genome due to the absence of cellular nucleosomes and high density of cognate binding sites. We posit that ICP4's ability to recruit not just Pol II, but also more limiting essential components, such as TBP and Mediator, create a competitive transcriptional environment. These distinguishing characteristics ultimately result in a rapid and efficient reprogramming of the host's transcriptional machinery, which does not occur in the absence of ICP4.
Highlights
Like most DNA viruses, the genome of Herpes simplex virus-1 (HSV-1) is transcribed by RNA Polymerase II (Pol II) (Alwine et al, 1974)
We propose that Infected Cell Polypeptide 4 (ICP4) is a major component of viral nucleoprotein, which functions in place of traditional cellular chromatin, and allows for the robust recruitment of cellular transcription factors to the viral genome
ICP4 binding is altered by viral genome replication
Summary
Like most DNA viruses, the genome of Herpes simplex virus-1 (HSV-1) is transcribed by RNA Polymerase II (Pol II) (Alwine et al, 1974). DNA replication licenses L promoters, enabling the binding of core Pol II transcription factors, activating the initiation of L transcription (Dremel and DeLuca, 2019) This entire transcriptional cascade is observed within 3 hours (h) post entry (Dembowski and DeLuca, 2018b; Dremel and DeLuca, 2019), culminating in production of the first viral progeny between 4 and 6 h post-infection (hpi). To accomplish this robust and rapidly changing program of transcription, the viral genome must compete with the vastly larger cellular genome for numerous Pol II transcription factors, in addition to mediating the possible constraints of cellular histones
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