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Two-step activation of ATM by DNA and the Mre11-Rad50-Nbs1 complex

Aude Dupré1, Louise Boyer-Chatenet, Jean Gautier

  • 1Columbia University, Department of Genetics and Development, HHSC1602, 701 West 168th Street, New York, New York 10032, USA.

Nature Structural & Molecular Biology
|April 20, 2006
PubMed

Insights

ATM protein kinase activation by DNA double-strand breaks (DSBs) involves two steps: recruitment to DNA and monomer conversion. The MRN complex aids initial recruitment, while Nbs1 drives catalytic activation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA double-strand breaks (DSBs) are critical DNA lesions.
  • ATM protein kinase activation is essential for cellular response to DSBs.
  • ATM coordinates cell-cycle arrest, DNA repair, and apoptosis.

Purpose of the Study:

  • To elucidate the two-step mechanism of ATM protein kinase activation by DSBs.
  • To clarify the roles of the MRN complex and Nbs1 in ATM activation.
  • To explain the molecular basis of related genetic disorders.

Main Methods:

  • Investigated ATM activation in response to DSBs.
  • Assessed the role of the MRN complex in ATM recruitment and activation.
  • Examined the function of the Nbs1 protein in ATM monomer conversion.

Main Results:

  • ATM activation occurs in two steps: recruitment to DNA and subsequent monomer activation.
  • The MRN complex facilitates ATM monomerization by tethering DNA.
  • The ATM-binding domain of Nbs1 is essential for converting ATM monomers into active kinases.

Conclusions:

  • A novel two-step model for ATM activation by DSBs is proposed.
  • This model explains ATM activation in normal cells and disease phenotypes.
  • Understanding ATM activation is crucial for therapeutic strategies targeting DNA repair pathways.

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