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Journal of Virology, August 2008, p. 7640-7652, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00170-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Role for E1B-AP5 in ATR Signaling Pathways during Adenovirus Infection{triangledown}

Andrew N. Blackford,1 Rachel K. Bruton,1 Orkide Dirlik,2 Grant S. Stewart,1 A. Malcolm R. Taylor,1 Thomas Dobner,2 Roger J. A. Grand,1 and Andrew S. Turnell1*

CR-UK Institute for Cancer Studies, The Medical School, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,1 Heinrich Pette Institut, University of Hamburg, Martinistrasse 52, 20251 Hamburg, Germany2

Received 24 January 2008/ Accepted 30 April 2008

E1B-55K-associated protein 5 (E1B-AP5) is a cellular, heterogeneous nuclear ribonucleoprotein that is targeted by adenovirus (Ad) E1B-55K during infection. The function of E1B-AP5 during infection, however, remains largely unknown. Given the role of E1B-55K targets in the DNA damage response, we examined whether E1B-AP5 function was integral to these pathways. Here, we show a novel role for E1B-AP5 as a key regulator of ATR signaling pathways activated during Ad infection. E1B-AP5 is recruited to viral replication centers during infection, where it colocalizes with ATR-interacting protein (ATRIP) and the ATR substrate replication protein A 32 (RPA32). Indeed, E1B-AP5 associates with ATRIP and RPA complex component RPA70 in both uninfected and Ad-infected cells. Additionally, glutathione S-transferase pull-downs show that E1B-AP5 associates with RPA components RPA70 and RPA32 directly in vitro. E1B-AP5 is required for the ATR-dependent phosphorylation of RPA32 during infection and contributes to the Ad-induced phosphorylation of Smc1 and H2AX. In this regard, it is interesting that Ad5 and Ad12 differentially promote the phosphorylation of RPA32, Rad9, and Smc1 during infection such that Ad12 promotes a significant phosphorylation of RPA32 and Rad9, whereas Ad5 only weakly promotes RPA32 phosphorylation and does not induce Rad9 phosphorylation. These data suggest that Ad5 and Ad12 have evolved different strategies to regulate DNA damage signaling pathways during infection in order to promote viral replication. Taken together, our results define a role for E1B-AP5 in ATR signaling pathways activated during infection. This might have broader implications for the regulation of ATR activity during cellular DNA replication or in response to DNA damage.

* Corresponding author. Mailing address: CR-UK Institute for Cancer Studies, The Medical School, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44-121-414-4483. Fax: 44-121-414-4486. E-mail: A.S.Turnell{at}bham.ac.uk

{triangledown} Published ahead of print on 14 May 2008.

Journal of Virology, August 2008, p. 7640-7652, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00170-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nichols, G. J., Schaack, J., Ornelles, D. A. (2009). Widespread Phosphorylation of Histone H2AX by Species C Adenovirus Infection Requires Viral DNA Replication. J. Virol. 83: 5987-5998 [Abstract] [Full Text]  
  • Blackford, A. N., Grand, R. J. A. (2009). Adenovirus E1B 55-Kilodalton Protein: Multiple Roles in Viral Infection and Cell Transformation. J. Virol. 83: 4000-4012 [Full Text]  


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