Functional interaction between DNA-PK and c-Abl in response to DNA damage

• Published in: Nature (London) 1997-04, Vol.386 (6626), p.732-735
• Main Authors: Kharbanda, Surender, Pandey, Pramod, Jin, Shengfang, Inoue, Satoshi, Bharti, Ajit, Yuan, Zhi-Min, Weichselbaum, Ralph, Weaver, David, Kufe, Donald
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Nuclear; Biochemistry; Biological and medical sciences; Cell Line; Deoxyribonucleic acid; DNA; DNA Damage; DNA Helicases; DNA-Activated Protein Kinase; DNA-Binding Proteins - metabolism; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Genetics; Genic rearrangement. Recombination. Transposable element; Humanities and Social Sciences; Ionizing radiation; Ku Autoantigen; letter; Mice; Molecular and cellular biology; Molecular genetics; multidisciplinary; Nuclear Proteins - metabolism; Phosphorylation; Protein Binding - radiation effects; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-abl - metabolism; Science; Science (multidisciplinary); src Homology Domains; Tyrosine - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/386732a0

How DNA damage is converted into intracellular signals that can control cell behaviour is unknown. The c-Abl protein tyrosine kinase is activated by ionizing radiation and certain other DNA-damaging agents 1–5 , whereas the DNA-dependent protein kinase (DNA-PK), consisting of a serine/threonine kinase and Ku DNA-binding subunits, requires DNA double-strand breaks or other DNA lesions for activation 6–8 . Here we demonstrate that c-Abl interacts constitutively with DNA-PK. Ionizing radiation stimulates binding of c-Abl to DNA-PK and induces an association of c-Abl with Ku antigen. We show that DNA-PK phosphorylates and activates c-Abl in vitro . Cells deficient in DNA-PK are defective in c-Abl activation induced by ionizing radiation. In a potential feedback mechanism, c-Abl phosphorylates DNA-PK, but not Ku, in vitro . Phosphorylation of DNA-PK by c-Abl inhibits the ability of DNA-PK to form a complex with DNA. We also show that treatment of cells with ionizing radiation results in phosphorylation of DNA-PK that is dependent on c-Abl. Our results support the hypothesis that there are functional interactions between c-Abl and DNA-PK in the response to DNA damage.