Abstract
The DNA-dependent protein kinase (DNA-PK) is composed of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer. DNA-PK is thought to act as the “sensor” for DNA double-stranded breaks (DSB), which are considered the most deleterious type of DNA damage. In particular, DNA-PKcs and Ku are shown to be essential for DSB repair through nonhomologous end joining (NHEJ). The phenotypes of animals and human individuals with defective DNA-PKcs or Ku functions indicate their essential roles in these developments, especially in neuronal and immune systems. DNA-PKcs are structurally related to Ataxia–telangiectasia mutated (ATM), which is also implicated in the cellular responses to DSBs. DNA-PKcs and ATM constitute the phosphatidylinositol 3-kinase-like kinases (PIKKs) family with several other molecules. Here, we review the accumulated knowledge on the functions of DNA-PKcs, mainly based on the phenotypes of DNA-PKcs-deficient cells in animals and human individuals, and also discuss its relationship with ATM in the maintenance of genomic stability.
Highlights
The DNA-dependent protein kinase (DNA-PK) is composed of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer
Carter et al and Lees-Miller et al purified this enzymatic activity from the nuclear extract of human cervical carcinoma HeLa cells and found it to be associated with a 300–350-kDa polypeptide, which is known as the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [2,3]
These discoveries indicated that DNA-PKcs and Ku are essential for double-stranded breaks (DSB) repair and V(D)J recombination
Summary
The first observation of DNA-dependent protein kinase (DNA-PK) activity dates back to 1985. Carter et al and Lees-Miller et al purified this enzymatic activity from the nuclear extract of human cervical carcinoma HeLa cells and found it to be associated with a 300–350-kDa polypeptide, which is known as the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [2,3]. Cells from SCID mice are sensitive to IR due to a reduced ability in DNA double-stranded break (DSB) repair [16]. Taccioli et al [18] and Smider et al [19] showed that Ku80 is inactivated in IR-sensitive and V(D)J recombination-defective hamster cells, such as xrs-5, XR-V15B and sxi-3 These discoveries indicated that DNA-PKcs and Ku are essential for DSB repair and V(D)J recombination. This historical perspectives have been reviewed more in detail elsewhere [20]
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