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DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) is an enzyme that in humans is encoded by the PRKDC gene. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. DNA-PKcs is the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase called DNA-PK. The second component is the autoimmune antigen Ku. On its own, DNA-PKcs is inactive and relies on Ku to direct it to DNA ends and trigger its kinase activity. DNA-PKcs is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Many proteins have been identified as substrates for the kinase activity of DNA-PK. Autophosphorylation of DNA-PKcs appears to play a key role in NHEJ and is thought to induce a conformational change that allows end processing enzymes to access the ends of the double-strand break. DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.