The Intrinsic Antiviral Defense to Incoming HSV-1 Genomes Includes Specific DNA Repair Proteins and Is Counteracted by the Viral Protein ICP0

Abstract

Cellular restriction factors responding to herpesvirus infection include the ND10 components PML, Sp100 and hDaxx. During the initial stages of HSV-1 infection, novel sub-nuclear structures containing these ND10 proteins form in association with incoming viral genomes. We report that several cellular DNA damage response proteins also relocate to sites associated with incoming viral genomes where they contribute to the cellular front line defense. We show that recruitment of DNA repair proteins to these sites is independent of ND10 components, and instead is coordinated by the cellular ubiquitin ligases RNF8 and RNF168. The viral protein ICP0 targets RNF8 and RNF168 for degradation, thereby preventing the deposition of repressive ubiquitin marks and counteracting this repair protein recruitment. This study highlights important parallels between recognition of cellular DNA damage and recognition of viral genomes, and adds RNF8 and RNF168 to the list of factors contributing to the intrinsic antiviral defense against herpesvirus infection.

Author Summary

The cellular DNA damage response pathway monitors damage to genomic DNA. We investigated whether cellular DNA damage response proteins can also respond to incoming viral genetic material and how they impact virus growth. Using Herpes Simplex Virus type 1 (HSV-1), we present evidence that DNA repair proteins are activated at the earliest times post-infection, and that they physically accumulate at sites associated with incoming viral genomes. A subset of these DNA repair proteins deposit repressive ubiquitin marks, recruit other DNA repair proteins, and limit transcription from the viral genomes. We demonstrate that the virus overcomes this anti-viral defense by targeting key DNA repair proteins for degradation. Our study adds these DNA repair protein mediators to the list of intrinsic antiviral defense factors active against HSV-1, and demonstrates that many aspects of the cellular recognition of foreign DNA parallel the recognition and response to cellular damage.