BINDING OF KU AND C-ABL AT THE KINASE HOMOLOGY REGION OF DNA-DEPENDENT PROTEIN-KINASE CATALYTIC SUBUNIT

The DNA-dependent protein kinase (DNA-PK) con trols the repair of doub le-stranded DNA breaks in mammalian cells. The protein kinase subunit of DNA-PK (DNA-PKcs) is targeted to DNA breaks by association with the Hu DNA-binding heterodimer. Here we show that a Ku association site i s present at the carboxyl terminus of DNA-PKcs (amino acids 3002-3850) near the protein kinase domain. Correspondingly, the nuclear c-Abl ty rosine kinase that associates with DNA-PK also binds to the kinase hom ology domain. The c-Abl SH3 domain binds to amino acids 3414-3850 of D NA-PKcs. c-Abl phosphorylates C-terminal fragments of DNA-PKcs, partic ularly amino acids 3414-3850. c-Abl phosphorylation of DNA-PKcs disass ociates the DNA-PKcs.Ku complex. Thus, Ku and c-Abl provide opposing f unctions with regard to DNA-PK activity.