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ATMIN defines an NBS1-independent pathway of ATM signalling

Nnennaya Kanu1, Axel Behrens

  • 1Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, UK.

The EMBO Journal
|May 26, 2007
PubMed

Insights

A newly identified protein, ATMIN, acts as an essential cofactor for ATM (ataxia telangiectasia mutated) kinase. ATMIN regulates ATM activity through a novel pathway independent of NBS1, impacting DNA damage response.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The ATM (ataxia telangiectasia mutated) kinase is crucial for transducing genomic stress signals, halting cell cycle progression, and promoting DNA repair following DNA damage.
  • Understanding ATM's regulatory mechanisms and cofactors is vital for comprehending cellular responses to genotoxic stress.

Purpose of the Study:

  • To characterize a newly identified ATM interacting protein, ATMIN (ATM INteracting protein), and elucidate its role in ATM signaling.
  • To investigate the relationship between ATMIN, ATM, and the known ATM cofactor NBS1 in DNA damage response pathways.

Main Methods:

  • Co-immunoprecipitation and co-localization studies to assess ATM-ATMIN interactions and localization under various stress conditions.
  • Analysis of ATM/ATMIN complex stability in cells with impaired NBS1 function.
  • Western blotting to evaluate protein levels of ATM and ATMIN in wild-type and knockout cells.
  • Assessment of ATM kinase activity and downstream signaling (phosphorylation of Smc1, Chk2, p53) in ATMIN-deficient cells.

Main Results:

  • ATMIN interacts with ATM via a C-terminal motif and co-localizes with ATM upon activation by chloroquine and hypotonic stress, but not ionizing radiation (IR).
  • IR disrupts the ATM/ATMIN complex, an effect attenuated by impaired NBS1 function, suggesting NBS1 and ATMIN compete for ATM binding.
  • ATMIN deficiency leads to reduced ATM protein levels, and ATMIN protein is reduced in ataxia telangiectasia cells, indicating reciprocal stabilization.
  • ATMIN-deficient cells exhibit impaired basal ATM activity and activation by hypotonic stress or DNA replication inhibition, despite normal IR-induced phosphorylation of key substrates like Chk2 and p53.

Conclusions:

  • ATMIN is an essential cofactor for ATM kinase, interacting with ATM through a motif also found in NBS1.
  • ATMIN plays a role in ATM stabilization and regulates ATM activity through a pathway that is distinct from and independent of NBS1.
  • These findings reveal a novel NBS1-independent pathway for ATM signaling, expanding our understanding of DNA damage response mechanisms.

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