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ATMINistrating ATM signalling: regulation of ATM by ATMIN

Nnennaya Kanu1, Axel Behrens

  • 1Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.

Cell Cycle (Georgetown, Tex.)
|November 13, 2008
PubMed

Insights

Researchers identified ATMIN as a crucial ATM cofactor. ATMIN and NBS1 compete for ATM binding, with ATMIN mediating responses to specific stresses, revealing new insights into DNA damage signaling.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • The ATM (ataxia telangiectasia mutated) kinase is a key regulator of the DNA damage response.
  • ATM signaling is crucial for halting cell cycle progression and initiating DNA repair pathways.
  • Identifying ATM cofactors is essential for understanding its complex signaling network.

Purpose of the Study:

  • To identify and characterize novel cofactors of ATM.
  • To elucidate the functional role of ATMIN (ATM INteractor) in ATM signaling.
  • To investigate the interplay between ATMIN, NBS1, and ATM in response to different DNA damaging agents.

Main Methods:

  • Co-immunoprecipitation assays to confirm physical interaction between ATMIN and ATM.
  • Analysis of protein stability to assess the functional relationship between ATMIN and ATM.
  • Cellular assays to evaluate ATM signaling in response to various stress conditions (e.g., chloroquine, hypotonic stress, ionizing radiation) in the presence or absence of ATMIN and NBS1.

Main Results:

  • ATMIN was identified as an essential cofactor for ATM.
  • ATMIN and ATM protein stability were mutually dependent, indicating a direct interaction.
  • ATMIN binds to ATM via its carboxy-terminal motif.
  • ATMIN and NBS1 exhibit complementary roles in ATM signaling, with ATMIN mediating responses to chloroquine and hypotonic stress, while NBS1 is critical for ionizing radiation-induced signaling.
  • Evidence suggests a competitive binding model between ATMIN and NBS1 for ATM.

Conclusions:

  • ATMIN is a novel and essential cofactor that plays a significant role in ATM signaling pathways.
  • The findings reveal a dynamic and signal-dependent interaction between ATM cofactors ATMIN and NBS1.
  • This study provides new insights into the regulatory mechanisms of ATM signaling in response to diverse genotoxic stresses.

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