Herpes simplex virus type I disrupts the ATR-dependent DNA-damage response during lytic infection.
Like other DNA viruses, herpes simplex virus type 1 (HSV-1) interacts with components of the cellular response to DNA damage. For example, HSV-1 sequesters endogenous, uninduced, hyperphosphorylated RPA (replication protein A) away from viral replication compartments. RPA is a ssDNA-binding protein that signals genotoxic stress through the ATR (ataxia telangiectasia-mutated and Rad3-related) pathway. The sequestration of endogenous hyperphosphorylated RPA away from replicating viral DNA suggests that HSV-1 prevents the normal ATR-signaling response. In this study we examine the spatial distribution of endogenous hyperphosphorylated RPA with respect to ATR, its recruitment factor, ATRIP, and the cellular dsDNA break marker, gammaH2AX, during HSV-1 infection. The accumulation of these repair factors at DNA lesions has previously been identified as an early event in signaling genotoxic stress. We show that HSV-1 infection disrupts the ATR pathway by a mechanism that prevents the recruitment of repair factors, spatially uncouples ATRIP from ATR and sequesters ATRIP and endogenous hyperphosphorylated RPA within virus-induced nuclear domains containing molecular chaperones and components of the ubiquitin proteasome. The HSV-1 immediate early protein ICP0 is sufficient to induce the redistribution of ATRIP. This is the first report that a virus can disrupt the usually tight colocalization of ATR and ATRIP.
Wilkinson
Dianna E
DE
Department of Molecular, Microbial and Structural Biology MC3205, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
Weller
Sandra K
SK
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005090:Exodeoxyribonucleases / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000378:metabolism* / Q000472:pathogenicity*; D006657:Histones / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051716:Replication Protein A / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014709:Vero Cells
C521194:ATRIP protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D017874:Immediate-Early Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D020033:Protein Isoforms; D051716:Replication Protein A; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1