The role of DNA-PK in aging and energy metabolism.

DNA-dependent protein kinase (DNA-PK) is a very large holoenzyme comprised of the p470 kDa DNA-PK catalytic subunit (DNA-PK ) and the Ku heterodimer consisting of the p86 (Ku 80) and p70 (Ku 70) subunits. It is best known for its nonhomologous end joining (NHEJ) activity, which repairs double-strand DNA (dsDNA) breaks (DSBs). As expected, the absence of DNA-PK activity results in sensitivity to ionizing radiation, which generates DSBs and defect in lymphocyte development, which requires NHEJ of the V(D)J region in the immunoglobulin and T-cell receptor loci. DNA-PK also has been reported to have functions seemingly unrelated to NHEJ. For example, DNA-PK responds to insulin signaling to facilitate the conversion of carbohydrates to fatty acids in the liver. More recent evidence indicates that DNA-PK activity increases with age in skeletal muscle, promoting mitochondrial loss and weight gain. These discoveries suggest that our understanding of DNA-PK is far from complete. As many excellent reviews have already been written about the role of DNA-PK in NHEJ, here we will review the non-NHEJ role of DNA-PK with a focus on its role in aging and energy metabolism.