Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
FEBS J. 2018 Jun;285(11):1959-1972. doi: 10.1111/febs.14410. Epub 2018 Mar 12.
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.
DNA 依赖性蛋白激酶（DNA-PK）是一种非常大的全酶，由 p470 kDa DNA-PK 催化亚基（DNA-PK）和由 p86（Ku80）和 p70（Ku70）亚基组成的 Ku 异二聚体组成。它以其非同源末端连接（NHEJ）活性而闻名，该活性可修复双链 DNA（dsDNA）断裂（DSBs）。不出所料，缺乏 DNA-PK 活性会导致对电离辐射的敏感性，电离辐射会产生 DSBs，并导致淋巴细胞发育缺陷，这需要在免疫球蛋白和 T 细胞受体基因座中进行 NHEJ。据报道，DNA-PK 还具有似乎与 NHEJ 无关的功能。例如，DNA-PK 响应胰岛素信号以促进肝脏中碳水化合物向脂肪酸的转化。最近的证据表明，DNA-PK 在骨骼肌中的活性随年龄的增长而增加，促进线粒体丧失和体重增加。这些发现表明，我们对 DNA-PK 的理解还远远不够。由于已经有许多关于 DNA-PK 在 NHEJ 中的作用的优秀综述，因此在这里我们将重点介绍 DNA-PK 在衰老和能量代谢中的非 NHEJ 作用。
