Abstract
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 agents1–5, 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 activation6–8. 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.
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References
Kharbanda, S. et al. Activation of the c-Abl tyrosine kinase in the cellular response to DNA-damaging agents. Nature 376, 785–788 ( 1995).
Kharbanda, S. et al. c-Abl activation regulates induction of the SEKl/stress activated protein kinase pathway in the cellular response to 1-α-D-arabinofuranosylcytosine. J. Biol. Chem. 270, 30278–30281 ( 1995).
Kharbanda, S. et al. The stress response to ionizing radiation involves c-Abl-dependent phosphoryl-ation of SHPTP1. Proc. Natl Acad. Sci. USA 93, 6898–6901 ( 1996).
Yuan, Z. M. et al. Role for the c-Abl tyrosine kinase in the growth arrest response to DNA damage. Nature 382, 272–274 ( 1996).
Liu, Z.-G. et al. Three distinct signalling responses by murine fibroblasts to genotoxic stress. Nature 384, 273–276 ( 1996).
Carter, T., Vancurova, I., Sun, I., Lou, W. & DeLeon, S. A DNA-activated protein kinase from HeLa cell nuclei. Mol. Cell. Biol. 10, 6460–6471 ( 1990).
Jackson, S. P., MacDonald, J. J., Lees-Miller, S. & Tjian, R. GC box binding induces phosphorylation of Spl by a DNA-dependent protein kinase. Cell 63, 155–165 ( 1990).
Lees-Miller, S. P., Chen, Y. & Anderson, C. W. Human cells contain a DNA-activated protein kinase that phosphorylates simian virus 40 T antigen, mouse p53 and the human Ku autoantigen. Mol. Cell. Biol. 10, 6472–6481 ( 1990).
Weaver, D. T. What to do at an end: DNA double-strand break repair. Trends Genet. 11, 388–392 ( 1995).
Lees-Miller, S. P. et al. Absence of p350 subunit of DNA-activated protein kinase form a radiosensitive human cell line. Science 267, 1183–1185 ( 1995).
Blunt, T. et al. Defective DNA-dependent protein kinase activity is linked to V(D) J recombination and DNA repair defects associated with the murine scid mutation. Cell 80, 813–823 ( 1995).
Kirchgessner, C. U. et al. DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science 267, 1178–1183 ( 1995).
Ren, R., Ye, Z.-S. & Baltimore, D. Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes Dev. 8, 783–795 ( 1994).
Feller, S., Ren, R., Hanafusa, H. & Baltimore, D. SH2 and SH3 domains as molecular adhesives: interactions of Crk and Abl. Trends Biochem. Sci. 19, 453–458 ( 1994).
Gottlieb, T. M. & Jackson, S. P. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72, 131–142 ( 1993).
Giffin, W. et al. Sequence-specific DNA binding by Ku autoantigen and its effects on transcription. Nature 380, 265–268 ( 1996).
Chan, D. W. & Lees-Miller, S. P. The DNA-dependent protein kinase is inactivated by autopho-sphorylation of the catalytic subunit. J. Biol. Chem. 271, 8936–8941 ( 1996).
Yuan, Z.-M. et al. Regulation of DNA damage-induced apoptosis by the c-Abl tyrosine kinase. Proc. Natl Acad. Sci. USA 94, 1437–1440 ( 1997).
Tybulewicz, V. L. J., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 ( 1991).
Banga, S. S., Hall, K. T., Sandhu, A. K., Weaver, D. T. & Athwal, R. S. Complementation of V(D)J recombination defect and x-ray sensitivity of scid mouse cells by human chromosome 8. J. Mutat. Res. 315, 239–247 ( 1994).
Hartley, K. O. et al. DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylino-sitol 3-kinase and the ataxia telangiectasia gene product. Cell 82, 849–856 ( 1995).
Boubnov, N. V. et al. Complementation of the ionozing radiation sensitivity, DNA end binding, and V(D)J recombination defects of double-strand break repair mutants by the p86 Ku autoantigen. Proc. Natl Acad. Sci. USA 92, 890–894 ( 1995).
Mayer, B. & Baltimore, D. Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase. Mol. Cell. Biol. 14, 2883–2894 ( 1994).
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Kharbanda, S., Pandey, P., Jin, S. et al. Functional interaction between DNA-PK and c-Abl in response to DNA damage. Nature 386, 732–735 (1997). https://doi.org/10.1038/386732a0
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DOI: https://doi.org/10.1038/386732a0
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