Ku, Artemis, and ataxia-telangiectasia-mutated: signalling networks in DNA damage.
Cell death linked to DNA damage has been implicated in various diseases caused by environmental stress and infection. Severe DNA damage, which is beyond the capacity of the DNA repair proteins, triggers apoptosis. Accumulation of DNA damage has been proposed to be a principal mechanism of infection, inflammation, cancer, and aging. The most deleterious form of DNA damage is double-strand breaks (DSBs), where ataxia-telangiectasia-mutated (ATM) is the main transducer of the double-strand DNA break signal. Once the DNA is damaged, the DNA repair protein Ku70/80 translocates into the nucleus, a process which may be mediated by ataxia-telangiectasia-mutated, a member of the phosphoinositide-3-kinase-like family. The function and stability of Artemis may also be regulated by ataxia-telangiectasia-mutated through its phosphorylation upon the occurrence of DNA damage. Interestingly, both Artemis and Ku70/80 are substrates of DNA-dependent protein kinase (DNA-PK), another member of the phosphoinositide-3-kinase-like family. In this review, we show how Ku and Artemis function in the DNA damage response and the ataxia-telangiectasia-mutated signaling pathway and discuss potential applications of agents targeting these DNA damage response molecules in the treatment of inflammation and cancer.
Morio
Tomohiro
T
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo 113-8519, Japan. tmorio.ped@tmd.ac.jp
Kim
Hyeyoung
H
D034961:Antigens, Nuclear / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004720:Endonucleases; D006801:Humans; D000072200:Ku Autoantigen; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C426344:DCLRE1C protein, human; D004720:Endonucleases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen