Henderson MJ, Munoz MA, Saunders DN, Clancy JL, Russell AJ, Williams B, Pappin D, Khanna KK, Jackson SP, Sutherland RL, Watts CK. (2006) EDD mediates DNA damage-induced activation of CHK2. J Biol Chem. 281(52):39990-40000.

EDD, the human orthologue of Drosophila melanogaster 'hyperplastic discs', is over-expressed or mutated in a number of common human cancers. Although EDD has been implicated in DNA damage signalling, a definitive role is 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 FHA domain and a region of EDD spanning a number of putative FHA-binding threonines. Using RNA interference, we demonstrate a critical role for EDD upstream of CHK2 in the DNA damage signalling pathway. EDD is necessary for the efficient activating phosphorylation of CHK2 in response to DNA damage following exposure to ionising 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 emphasise the potential importance of EDD in cancer.