Article
- The EMBO Journal (2009) 28, 652 - 662
- doi:10.1038/emboj.2009.15
Published online: 5 February 2009
Subject Categories:
Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection
Christian T Carson1,2,ab, Nicole I Orazio1,2,a, Darwin V Lee1,ac, Junghae Suh1,d, Simon Bekker-Jensen3, Felipe D Araujo1,b, Seema S Lakdawala1,2, Caroline E Lilley1, Jiri Bartek3, Jiri Lukas3 and Matthew D Weitzman1
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA
- Graduate Program, Division of Biology, University of California, San Diego, CA, USA
- Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark
Correspondence to:
Matthew D Weitzman, Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA. Tel.: +858 453 4100 Ext 2037; Fax: +858 558 7454; E-mail: weitzman@salk.edu
aThese authors contributed equally to this work
bPresent address: Becton Dickinson Biosciences, San Diego, CA, USA
cPresent address: Pfizer, Groton, CT, USA
dPresent address: Department of Bioengineering, Rice University, Houston, TX, USA
Received 18 August 2008; Accepted 23 December 2008
Abstract
The protein kinases ataxia-telangiectasia mutated (ATM) and ATM-Rad3 related (ATR) are activated in response to DNA damage, genotoxic stress and virus infections. Here we show that during infection with wild-type adenovirus, ATR and its cofactors RPA32, ATRIP and TopBP1 accumulate at viral replication centres, but there is minimal ATR activation. We show that the Mre11/Rad50/Nbs1 (MRN) complex is recruited to viral centres only during infection with adenoviruses lacking the early region E4 and ATR signaling is activated. This suggests a novel requirement for the MRN complex in ATR activation during virus infection, which is independent of Mre11 nuclease activity and recruitment of RPA/ATR/ATRIP/TopBP1. Unlike other damage scenarios, we found that ATM and ATR signaling are not dependent on each other during infection. We identify a region of the viral E4orf3 protein responsible for immobilization of the MRN complex and show that this prevents ATR signaling during adenovirus infection. We propose that immobilization of the MRN damage sensor by E4orf3 protein prevents recognition of viral genomes and blocks detrimental aspects of checkpoint signaling during virus infection.
Keywords:
- adenovirus,
- ATR kinase,
- DNA damage response,
- MRN complex
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