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ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex

Ji-Hoon Lee1, Tanya T Paull

  • 1Department of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, 1 University Station, A4800, Austin, TX 78712, USA.

Science (New York, N.Y.)
|March 26, 2005
PubMed

Insights

The Mre11-Rad50-Nbs1 (MRN) complex senses DNA double-strand breaks and recruits the ataxia-telangiectasia mutated (ATM) kinase. MRN unwinds DNA ends, activating ATM to trigger DNA repair pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The ataxia-telangiectasia mutated (ATM) kinase is a crucial sensor of DNA double-strand breaks (DSBs) in mammalian cells.
  • ATM activation initiates cell-cycle arrest, apoptosis, and DNA repair pathways by phosphorylating downstream targets.

Purpose of the Study:

  • To elucidate the role of the Mre11-Rad50-Nbs1 (MRN) complex in ATM activation.
  • To investigate the mechanism by which MRN interacts with ATM at DSBs.

Main Methods:

  • In vitro biochemical assays to study ATM activation in the presence of MRN and DNA.
  • Analysis of ATM autophosphorylation and phosphorylation of downstream targets like p53 and Chk2.

Main Results:

  • The MRN complex acts as a direct sensor for DSBs and recruits ATM to broken DNA sites.
  • MRN facilitates ATM activation by unwinding DNA ends, independent of ATM autophosphorylation.
  • Activated ATM phosphorylates downstream targets p53 and Chk2, confirming functional activation.

Conclusions:

  • The MRN complex is essential for sensing DNA double-strand breaks and recruiting ATM.
  • DNA end unwinding by MRN is a critical step for ATM activation, highlighting the role of single-stranded DNA in DNA damage signaling.

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