Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection.
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.
Carson
Christian T
CT
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Orazio
Nicole I
NI
Lee
Darwin V
DV
Suh
Junghae
J
Bekker-Jensen
Simon
S
Araujo
Felipe D
FD
Lakdawala
Seema S
SS
Lilley
Caroline E
CE
Bartek
Jiri
J
Lukas
Jiri
J
Weitzman
Matthew D
MD
D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae / Q000502:physiology; D000257:Adenoviridae Infections / Q000378:metabolism*; D017504:Adenovirus E4 Proteins / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D000076228:MRE11 Homologue Protein; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014779:Virus Replication
D017504:Adenovirus E4 Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D046912:Multiprotein Complexes; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes