Abstract
During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional control. This review summarizes the array of impacts that HSV has on RNA Polymerase (Pol) II, which transcribes all mRNA in infected cells. We discuss alterations in Pol II holoenzymes, post-translational modifications, and how viral proteins regulate specific activities such as promoter-proximal pausing, splicing, histone repositioning, and termination with respect to host genes. Recent technological innovations that have reshaped our understanding of previous observations are summarized in detail, along with specific research directions and technical considerations for future studies.
Highlights
What is unique to herpes simplex virus (HSV), is the multitude of cellular transcriptional events the virus antagonizes on host chromatin while simultaneously preserving these activities on viral genes
This study identified three viral immediate-early proteins—ICP0, ICP4 and ICP27—that co-eluted with Pol II, predominately in the lower molecular weight fractions
Though it is clear that ICP4 reduces Pol II occupancy on host genes, it remains to be determined at what point transcription factors become unavailable to host genes from the nucleoplasm or recycling from more proximal chromatin
Summary
Herpes simplex virus type 1 (HSV-1) is the cause of the common cold sore as well as a leading agent in infectious blindness and is capable of establishing severe skin lesions in addition to life-threatening encephalitis. Though it is clear that ICP4 reduces Pol II occupancy on host genes, it remains to be determined at what point transcription factors become unavailable to host genes from the nucleoplasm or recycling from more proximal chromatin This would clarify activities of viral proteins beyond the competition that inhibit promoter recruitment during the earliest stages of lytic infection or latent reactivation. Another area of interest is exploring how Pol. II condensates around sites of active cellular transcription are affected by HSV, either by the action of viral proteins or by physical rearrangement of nuclear structures and host chromatin, as these sites can regulate gene expression in ways not readily apparent by sequencing-based approaches
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