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Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection

Christian T Carson1, Nicole I Orazio, Darwin V Lee

  • 1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

The EMBO Journal
|February 7, 2009
PubMed

Insights

Adenovirus infection prevents ATR signaling by immobilizing the MRN complex. This mechanism, mediated by the viral E4orf3 protein, avoids detrimental DNA damage responses during infection.

Area of Science:

  • Molecular Biology
  • Virology
  • Cellular Biology

Background:

  • Protein kinases ataxia-telangiectasia mutated (ATM) and ATM-Rad3 related (ATR) are crucial for DNA damage response and stress signaling.
  • Virus infections can trigger cellular stress responses, but viruses often possess mechanisms to evade or manipulate these pathways.

Purpose of the Study:

  • To investigate the activation and localization of ATR signaling during adenovirus infection.
  • To elucidate the role of the Mre11/Rad50/Nbs1 (MRN) complex in ATR activation during viral infections.
  • To identify viral factors that modulate ATR signaling.

Main Methods:

  • Immunofluorescence microscopy to visualize protein localization at viral replication centers.
  • Western blotting to assess protein activation and signaling pathways.
  • Genetic manipulation of adenovirus (E4 deletion mutants) to study the role of viral proteins.

Main Results:

  • ATR and its cofactors accumulate at adenovirus replication centers but show minimal activation during wild-type infection.
  • The MRN complex is recruited to viral centers and ATR signaling is activated only in adenoviruses lacking the E4 region.
  • Adenovirus E4orf3 protein directly immobilizes the MRN complex, preventing ATR activation and signaling.
  • ATM and ATR signaling pathways operate independently during adenovirus infection.

Conclusions:

  • The MRN complex is essential for ATR activation during adenovirus infection, independent of its nuclease activity.
  • Adenovirus E4orf3 protein actively suppresses ATR signaling by sequestering the MRN complex.
  • This viral strategy prevents detrimental DNA damage responses, allowing efficient viral replication.

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