DNA-Dependent Protein Kinase (DNA-PK) Inhibitors
DNA-dependent protein kinase (DNA-PK) is a trimeric nuclear serine/threonine kinase composed of a large catalytic subunit and two DNA-targeting proteins, Ku70 and Ku80. The catalytic subunit, by itself, is inactive. It relies on other DNA-PK components to direct it to the DNA and trigger its kinase activity. The amino acid sequence of the DNA-PK suggests that it is a member of the phosphatidylinositol-3-kinase (PI 3-K) superfamily. DNA-PK recognizes and initiates repair of DNA double-strand breaks produced by ionizing radiation and certain drugs.
DNA-PK phosphorylates protein targets and also undergoes auto-phosphorylation. The auto-phosphorylation activity has been shown to be essential for repair of random double-strand breaks. DNA-PK phosphorylates p53 on Ser115 and Ser37 leading to stabilization and inhibition of p53 degradation by MDM2. Phosphorylation of Ser15 is suggested to be essential for p53 function. Ser15 resides within the critical N-terminal region of p53, which controls the interaction of p53 with the transcriptional apparatus and with the MDM2 protein. Phosphorylation of Ser15 weakens both the association of p53 with MDM2 and the repression of p53 by MDM2. Phosphorylation of DNA-PK by the PKCδ catalytic fragment leads to the dissociation of DNA-PK from DNA, resulting in its inactivation. More recently, DNA-PK has been reported to suppress also a p53-independent apoptotic response to DNA damage.
DNA-PK represents a new target for cancer drug development. Cells defective in DNA-PK components are reported to be hypersensitive to killing by ionizing radiation owing to their inability to repair double-stranded breaks effectively. A number of small molecule inhibitors of DNA-PK catalytic subunit have been developed, which sensitize cells to DNA-damaging agents, but are relatively nontoxic in the absence of DNA breaks. These inhibitors may have clinical potential in the treatment of cancer.
Gurley, K.E. et al. 2008. EMBO Reports 10, 87.
Collis, S.J., et al. 2005. Oncogene 24, 949.
Wechsler, T., et al. 2004. Proc. Natl. Acad. Sci. USA 101, 1247.
Basu, A., 2003. J. Cell. Mol. Med. 7, 341.
Kashishian, A., et al. 2003. Mol. Cancer Ther. 2, 1257.
Woo, R.A., et al. 1998. Nature 394, 700.
Jackson, S.P., and Jeggo, P.A. 1995. Trends Biochem. Sci. 20, 412.