DNA-activated protein kinase (DNA-PK) is a serine/threonine protein kinase that interacts with a DNA end-binding heterodimeric protein, Ku, and is activated by double-stranded DNA. Genomic clones that contain the DNA-PK gene complement the murine scid defect, indicating that DNA-PK affects double-strand break repair and V(D)J recombination. Here we describe the cDNA sequence of the region that corresponds to about 100 kDa of C-terminal sequence of this large (> p350 kDa) protein. This region contains a kinase domain that has strong homology to phosphatidylinositol kinases.