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EDD mediates DNA damage-induced activation of CHK2.

EDD, the human orthologue of Drosophila melanogaster "hyperplastic discs," is overexpressed or mutated in a number of common human cancers. Although EDD has been implicated in DNA damage signaling, a definitive role has yet to be demonstrated. Here we report a novel interaction between EDD and the DNA damage checkpoint kinase CHK2. EDD and CHK2 associate through a phospho-dependent interaction involving the CHK2 Forkhead-associated domain and a region of EDD spanning a number of putative Forkhead-associated domain-binding threonines. Using RNA interference, we demonstrate a critical role for EDD upstream of CHK2 in the DNA damage signaling pathway. EDD is necessary for the efficient activating phosphorylation of CHK2 in response to DNA damage following exposure to ionizing radiation or the radiomimetic, phleomycin. Cells depleted of EDD display impaired CHK2 kinase activity and an inability to respond to DNA damage. These results identify EDD as a novel mediator in DNA damage signal transduction via CHK2 and emphasize the potential importance of EDD in cancer.

Pubmed ID: 17074762

Authors

  • Henderson MJ
  • Munoz MA
  • Saunders DN
  • Clancy JL
  • Russell AJ
  • Williams B
  • Pappin D
  • Khanna KK
  • Jackson SP
  • Sutherland RL
  • Watts CK

Journal

The Journal of biological chemistry

Publication Data

December 29, 2006

Associated Grants

None

Mesh Terms

  • Cell Line
  • Cell Line, Tumor
  • Checkpoint Kinase 2
  • DNA Damage
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Ubiquitin-Protein Ligases