ATR and ATRIP are recruited to herpes simplex virus type 1 replication compartments even though ATR signaling is disabled.

Mohni KN, Livingston CM, Cortez D, Weller SK
J Virol. 2010 84 (23): 12152-64

PMID: 20861269 · PMCID: PMC2976399 · DOI:10.1128/JVI.01643-10

Although the herpes simplex virus type 1 (HSV-1) genome might be expected to induce a DNA damage response, the ATR kinase is not activated in infected cells. We previously proposed that spatial uncoupling of ATR from its interaction partner, ATRIP, could be the basis for inactivation of the ATR kinase in infected cells; however, we now show that ATR and ATRIP are in fact both recruited to HSV-1 replication compartments and can be coimmunoprecipitated from infected-cell lysates. ATRIP and replication protein A (RPA) are recruited to the earliest detectable prereplicative sites, stage II microfoci. In a normal cellular DNA damage response, ATR/ATRIP are recruited to stretches of RPA-coated single-stranded DNA in an RPA- and kinase-dependent manner, resulting in the phosphorylation of RPA by ATR in damage foci. In contrast, in HSV-1-infected cells, RPA is not phosphorylated, and endogenous phosphorylated RPA is excluded from stage II microfoci; in addition, the recruitment of ATR/ATRIP is independent of RPA and the kinase activity of ATR. Furthermore, we show that ATR/ATRIP play a beneficial role in viral gene expression and virus production. Although ICP0 has been shown to be important for partial inactivation of other cellular DNA repair pathways, we show that ICP0 is not responsible for the inactivation of ATR signaling and, furthermore, that neither ATR nor ATRIP is a target of ICP0 degradation. Thus, ATR and ATRIP may function outside the context of the canonical ATR damage signaling pathway during HSV-1 infection to participate in the viral life cycle.

MeSH Terms (23)

Adaptor Proteins, Signal Transducing Animals Ataxia Telangiectasia Mutated Proteins Blotting, Western Cell Cycle Proteins Cercopithecus aethiops DNA-Binding Proteins DNA Damage DNA Primers Fluorescent Antibody Technique HeLa Cells Herpesvirus 1, Human Humans Immediate-Early Proteins Immunoprecipitation Phosphorylation Plasmids Protein-Serine-Threonine Kinases Replication Protein A Signal Transduction Ubiquitin-Protein Ligases Vero Cells Virus Replication

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