Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Activation of the cellular DNA damage response is detrimental to adenovirus (Ad) infection. Ad has therefore evolved a number of strategies to inhibit ATM- and ATR-dependent signaling pathways during infection. Recent work suggests that the Ad5 E4orf3 protein prevents ATR activation through its ability to mislocalize the MRN complex. Here we provide evidence to indicate that Ad12 has evolved a different strategy from Ad5 to inhibit ATR. We show that Ad12 utilizes a CUL2/RBX1/elongin C-containing ubiquitin ligase to promote the proteasomal degradation of the ATR activator protein topoisomerase-IIbeta-binding protein 1 (TOPBP1). Ad12 also uses this complex to degrade p53 during infection, in contrast to Ad5, which requires a CUL5-based ubiquitin ligase. Although Ad12-mediated degradation of p53 is dependent upon both E1B-55K and E4orf6, Ad12-mediated degradation of TOPBP1 is solely dependent on E4orf6. We propose that Ad12 E4orf6 has two principal activities: to recruit the CUL2-based ubiquitin ligase and to act as substrate receptor for TOPBP1. In support of the idea that Ad12 E4orf6 specifically prevents ATR activation during infection by targeting TOPBP1 for degradation, we demonstrate that Ad12 E4orf6 can inhibit the ATR-dependent phosphorylation of CHK1 in response to replication stress. Taken together, these data provide insights into how Ad modulates ATR signaling pathways during infection.

Original publication

DOI

10.1073/pnas.0914605107

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

06/07/2010

Volume

107

Pages

12251 - 12256

Keywords

Adenoviridae, Adenovirus E1B Proteins, Ataxia Telangiectasia Mutated Proteins, Blotting, Western, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Checkpoint Kinase 1, Cullin Proteins, DNA-Binding Proteins, Elongin, Fluorescent Antibody Technique, HeLa Cells, Host-Pathogen Interactions, Humans, Microscopy, Confocal, Mutation, Nuclear Proteins, Phosphorylation, Proteasome Endopeptidase Complex, Protein Kinases, Protein-Serine-Threonine Kinases, RNA Interference, Transcription Factors, Transfection, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Viral Proteins