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ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage

David Dornan1, Harumi Shimizu, Angie Mah

  • 1Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Science (New York, N.Y.)
|August 26, 2006
PubMed

Insights

The ataxia telangiectasia mutated (ATM) protein kinase regulates the COP1-p53 axis after DNA damage. ATM phosphorylation of COP1 on Ser(387) disrupts COP1-p53 binding, stabilizing p53 and its tumor suppressor functions.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • The ataxia telangiectasia mutated (ATM) protein kinase is crucial for DNA damage response and genomic integrity.
  • Tumor suppressor protein p53 stability is regulated by E3 ubiquitin ligases, including COP1, but the ATM-regulated pathway is unclear.

Purpose of the Study:

  • To elucidate the signal transduction pathway regulating the COP1-p53 axis following DNA damage.
  • To investigate the role of ATM in the regulation of COP1 and p53.

Main Methods:

  • Studied the effect of DNA damage on ATM, COP1, and p53 interactions and localization.
  • Utilized ionizing radiation to induce DNA damage and analyzed COP1 phosphorylation at Ser(387).

Main Results:

  • ATM phosphorylates COP1 on Ser(387) in response to DNA damage, triggering COP1 autodegradation.
  • Ionizing radiation induces ATM-dependent nuclear-to-cytoplasmic translocation of COP1.
  • Phosphorylation of COP1 on Ser(387) by ATM disrupts the COP1-p53 complex, preventing p53 ubiquitination and degradation.

Conclusions:

  • ATM-dependent phosphorylation of COP1 on Ser(387) is essential for p53 stabilization and tumor suppressor activity after DNA damage.
  • This pathway represents a novel mechanism for regulating p53 function in response to genomic stress.

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