A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses.
The ICP0 protein of herpes simplex virus type 1 is an E3 ubiquitin ligase and transactivator required for the efficient switch between latent and lytic infection. As DNA damaging treatments are known to reactivate latent virus, we wished to explore whether ICP0 modulates the cellular response to DNA damage. We report that ICP0 prevents accumulation of repair factors at cellular damage sites, acting between recruitment of the mediator proteins Mdc1 and 53BP1. We identify RNF8 and RNF168, cellular histone ubiquitin ligases responsible for anchoring repair factors at sites of damage, as new targets for ICP0-mediated degradation. By targeting these ligases, ICP0 expression results in loss of ubiquitinated forms of H2A, mobilization of DNA repair proteins and enhanced viral fitness. Our study raises the possibility that the ICP0-mediated control of histone ubiquitination may link DNA repair, relief of transcriptional repression, and activation of latent viral genomes.
Lilley
Caroline E
CE
The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Chaurushiya
Mira S
MS
Boutell
Chris
C
Landry
Sebastien
S
Suh
Junghae
J
Panier
Stephanie
S
Everett
Roger D
RD
Stewart
Grant S
GS
Durocher
Daniel
D
Weitzman
Matthew D
MD
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015151:Immunoblotting; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology; D014709:Vero Cells
D004268:DNA-Binding Proteins; D006657:Histones; D017874:Immediate-Early Proteins; C486521:RNF8 protein, human; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1