Inactivation of DNA-dependent protein kinase by protein kinase Cδ:: Implications for apoptosis

Protein kinase CS (PKC delta) is proteolytically cleaved and activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Pas antibody. A role for PKC delta in apoptosis is supported by the finding that overexpression of the catalytic fragment of PKC delta (PKC delta CF) in cells is associated with the appearance of certain characteristics of apoptosis. However, the functional relationship between PKC delta cleavage and induction of apoptosis is unknown. The present studies demonstrate that PKC delta associates constitutively with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The results show that PKC delta CF phosphorylates DNA-PKcs in vitro. Interaction of DNA-PKcs with PKC delta CF inhibits the function of DNA-PKcs to form complexes with DNA and to phosphorylate its downstream target, p53. The results also demonstrate that cells deficient in DNA-PK are resistant to apoptosis induced by overexpressing PKC delta CF. These findings support the hypothesis that functional interactions between PKC delta and DNA-PK contribute to DNA damage-induced apoptosis.