FUNCTIONAL INTERACTION BETWEEN DNA-PK AND C-ABL IN RESPONSE TO DNA-DAMAGE

How DNA damage is converted into intracellular signals that can contro l cell behaviour is unknown. The c-Abl protein tyrosine kinase is acti vated by ionizing radiation and certain other DNA-damaging agents(1-5) , whereas the DNA-dependent protein kinase (DNA-PK), consisting of a s erine/threonine kinase and Ku DNA-binding subunits, requires DNA doubl e-strand breaks or other DNA lesions for activation(6-8). Here we demo nstrate that c-Abl interacts constitutively with DNA-PK. Ionizing radi ation stimulates binding of c-Abl to DNA-PK and induces an association of c-Abl with Ku antigen. We show that DNA-PK phosphorylates and acti vates c-Abl in vitro. Cells deficient in DNA-PK are defective in c-Abl activation induced by ionizing radiation. In a potential feedback mec hanism, c-Abl phosphorylates DNA-PK, but not Ku, in vitro. Phosphoryla tion of DNA-PK by c-Abl inhibits the ability of DNA-PK to form a compl ex with DNA. We also show that treatment of cells with ionizing radiat ion results in phosphorylation of DNA-PK that is dependent on c-Abl. O ur results support the hypothesis that there are functional interactio ns between c-Abl and DNA-PK in the response to DNA damage.