The DNA dependent protein kinase: a major protein involved in the cellularresponse to ionizing radiation

DNA-dependent protein,kinase (DNA-PK) is a DNA-activated nuclear serine/thr eonine protein kinase. DNA-PK consists of a regulatory sub-unit, the hetero dimeric Ku protein (composed of a 70- and a 86-kDa subunit) which binds DNA ends and targets the catalytic sub-unit, DNA-PKcs to DNA strand breaks. DN A-PK plays a major role in the repair of double-strand breaks induced in DN A after exposure to ionizing radiation as shown by the extreme radiosensiti vity of cells with mutations in Ku86, Ku70 or DNA-PKcs genes. Cells deficie nt in DNA-PK activity also exhibit hypersensitivity to genotoxic drugs such as cisplatin and nitrogen mustards. In the first part of this review, the current knowledge on the biochemical characteristics of DNA-PK; its mechani sm of action in DNA repair and the phenotype of DNA-PK deficient cells is s ummarized. These results suggest that DNA-PK might play a role in the acqui sition of a resistant phenotype of human tumors to radiotherapy, chemothera py using genotoxic drugs or to both treatments. In the second part of this review, the studies devoted to inhibition of DNA-PK in order to enhance can cer therapy by DNA-damaging agents are presented.