Journal
JOURNAL OF CELL SCIENCE
Volume 119, Issue 13, Pages 2695-2703Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.02981
Keywords
herpesvirus; ICP0; DNA-damage response; ATR; ATRIP; hyperphosphorylated RPA; phosphorylated H2AX; chaperones; proteasome
Categories
Funding
- NIAID NIH HHS [R01 AI021747, R01 AI069136, R37 AI021747, R01 AI069136-01, F32 AI054042, AI21747] Funding Source: Medline
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Like other DNA viruses, herpes simplex virus type 1 (HSV1) 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, gamma H2AX, 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.
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