Oh HS, Neuhausser WM, Eggan P, Angelova M, Kirchner R, Eggan KC, Knipe DM. 2019. Herpesviral lytic gene functions render the viral genome susceptible to novel editing by CRISPR/Cas9. eLife. 8. Pubmed: 31789594 DOI:e51662


Herpes simplex virus (HSV) establishes lifelong latent infection and can cause serious human disease, but current antiviral therapies target lytic but not latent infection. We screened for sgRNAs that cleave HSV-1 DNA sequences efficiently in vitro and used these sgRNAs to observe the first editing of quiescent HSV-1 DNA. The sgRNAs targeted lytic replicating viral DNA genomes more efficiently than quiescent genomes, consistent with the open structure of lytic chromatin. Editing of latent genomes caused short indels while editing of replicating genomes produced indels, linear molecules, and large genomic sequence loss around the gRNA target site. The HSV ICP0 protein and viral DNA replication increased the loss of DNA sequences around the gRNA target site. We conclude that HSV, by promoting open chromatin needed for viral gene expression and by inhibiting the DNA damage response, makes the genome vulnerable to a novel form of editing by CRISPR-Cas9 during lytic replication.
© 2019, Oh et al.

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Kevin Eggan investigates the mechanisms that cause motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS), and seeks to translate new discoveries into new therapeutic options for patients.

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