DNAPK

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase in the phosphatidylinositol 3-kinase-related kinase (PIKK) family. It forms a holoenzyme consisting of a catalytic subunit, DNA-PKcs, and a Ku heterodimer (Ku70/Ku80) that binds to DNA ends. The enzyme is encoded by the PRKDC gene in humans.

DNA-PK plays a central role in the non-homologous end joining (NHEJ) pathway for repairing DNA double-strand breaks. Upon binding of Ku to DNA ends, DNA-PKcs is recruited and activated. Autophosphorylation of DNA-PKcs induces conformational changes that allow processing of DNA ends by nucleases such as Artemis, after which the ligation step is completed by the Ligase IV–XRCC4–XLF complex. DNA-PK also phosphorylates several substrates to coordinate repair and signaling.

In addition to DNA repair, DNA-PKcs is required for V(D)J recombination, a process generating antigen receptor diversity in developing B and T cells, linking DNA repair to immune system development. Deficiency in DNA-PKcs impairs lymphocyte development and leads to radiosensitivity in model organisms and, in rare cases, humans.

As a therapeutic target, DNA-PK inhibitors are investigated to increase the sensitivity of cancer cells to radiation and DNA-damaging chemotherapy. Compounds such as NU7441, M3814 (peposertib), and others have been studied in preclinical and clinical settings, though selectivity and toxicity profiles vary.