DNA-DEPENDENT PROTEIN-KINASE CATALYTIC SUBUNIT - A RELATIVE OF PHOSPHATIDYLINOSITOL 3-KINASE AND THE ATAXIA-TELANGIECTASIA GENE-PRODUCT

DNA-dependent protein kinase (DNA-PK), which is involved in DNA double -stranded break repair and V(D)J recombination, comprises a DNA-target ing component called Ku and an similar to 460 kDa catalytic subunit, D NA-PKcs. Here, we describe the cloning of the DNA-PKcs cDNA and show t hat DNA-PKcs falls into the phosphatidylinositol (PI) 3-kinase family. Biochemical assays, however, indicate that DNA-PK phosphorylates prot eins but has no detectable activity toward lipids, Strikingly, DNA-PKc s is most similar to PI kinase family members involved in cell cycle c ontrol, DNA repair, and DNA damage responses. These include the FKBP12 -rapamycin-binding proteins Tor1p, Tor2p, and FRAP, S. pombe rad3, and the product of the ataxia telangiectasia gene, mutations in which lea d to genomic instability and predisposition to cancer. The relationshi p of these proteins to DNA-PKcs provides important clues to their mech anisms of action.