DNA-PK is a trimeric enzyme that is composed of a catalytic subunit of ~ 465 kDa (DNA-PKcs) and a heterodimeric regulatory subunit of 70 kDa and 86 kDa. DNA-PKcs has been reported to be inactive alone and depends on the regulatory subunit for subcellular localization and kinase activity. DNA-PKcs belongs to the phosphatidylinositol (PI)3-kinase family and phosphorylates proteins, particularly transcription factors, but not lipids. It is most similar to the members of this family that regulate cell cycle control, DNA repair, and DNA damage. DNA-PKcs and Ku80 are involved in V(D)J recombination and DNA double-stranded break repair mechanisms. The immunodeficiency disorder SCID is the result of abnormal V(D)J recombination in T lymphocytes. In SCID mice, a portion of the DNA-PKcs C-terminal phosphatidylinositol 3-kinase domain is deleted due to a T to A nucleotide transversion that produces a premature stop codon and a truncated protein product. Thus, the mutated gene for DNA-PKcs may be the SCID gene.