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The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response

Jan Karlseder1, Kristina Hoke, Olga K Mirzoeva

  • 1Laboratory for Cell Biology and Genetics, Rockefeller University, New York, USA.

Plos Biology
|August 18, 2004
PubMed

Insights

The telomeric protein TRF2 prevents DNA damage responses at telomeres. Overexpressing TRF2 inhibits ATM kinase activation, blocking cell cycle arrest and DNA damage signaling specifically at chromosome ends.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Telomeres are crucial for chromosome stability.
  • The telomeric protein TRF2 (Telomere Repeat Binding Factor 2) prevents inappropriate DNA damage responses at telomeres.
  • The ATM (Ataxia Telangiectasia Mutated) kinase is a key regulator of the DNA damage response.

Purpose of the Study:

  • To investigate the role of TRF2 in regulating the ATM kinase response to DNA damage.
  • To determine if TRF2 affects ATM activation at telomeres.

Main Methods:

  • Overexpression of TRF2 in mammalian cells.
  • Exposure to ionizing radiation.
  • Analysis of cell cycle progression.
  • Measurement of DNA damage response markers (Nbs1 phosphorylation, p53 induction).
  • In vitro interaction studies between ATM and TRF2.

Main Results:

  • Overexpression of TRF2 abrogated ionizing radiation-induced cell cycle arrest.
  • TRF2 overexpression diminished Nbs1 phosphorylation, p53 induction, and p53 target gene upregulation.
  • TRF2 inhibited ATM autophosphorylation at S1981.
  • TRF2 directly interacted with ATM in vitro and was found in ATM immunoprecipitates.

Conclusions:

  • TRF2 inhibits ATM activation at telomeres.
  • This mechanism allows for specific suppression of DNA damage responses at chromosome ends without compromising surveillance of internal DNA damage.

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