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J. Biol. Chem., Vol. 278, Issue 24, 22136-22143, June 13, 2003

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Novel Localization of the DNA-PK Complex in Lipid Rafts

A PUTATIVE ROLE IN THE SIGNAL TRANSDUCTION PATHWAY OF THE IONIZING RADIATION RESPONSE^*

Hector Lucero , Darren Gae  and Guillermo E. Taccioli  ¶

From the Departments of Molecular and Cellular Biology, Goldman School of Dental Medicine, Boston University, Boston, Massachusetts 02118, Department of Microbiology, School of Medicine, Boston University, Boston, Massachusetts 02118

Increased sensitivity to ionizing radiation (IR) has been shown to be due to defects in DNA double-strand break repair machinery. The major pathway in mammalian cells dedicated to the repair of DNA double-strand breaks is by the nonhomologous end-joining machinery. Six components function in this pathway, of which three (Ku70, Ku86, and DNA-PKcs) constitute a protein complex known as DNA-dependent protein kinase (DNA-PK). However, it is now recognized that the cellular radiation response is complex, and radiosensitivity may be also regulated at different levels in the radiation signal transduction pathway. In addition to DNA damage, exposure to IR triggers intracellular signaling cascades that overlap with pathways initiated by ligand engagement to a receptor. In this study, we provide evidence for the novel localization of the DNA-PK complex in lipid rafts. We also show this property is not a generalized characteristic of all DNA repair proteins. Furthermore, we have detected Ku86 in yeast lipid rafts. Our results suggest that the components of this complex might be recruited separately to the plasma membrane by tethering with raft-resident proteins. In addition, we found an irradiation-induced differential protein phosphorylation pattern dependent upon DNA-PKcs in lipid rafts. Thus, we speculate that another role for the DNA-PKcs subunit and perhaps for the holoenzyme is in the signal transduction of IR response.

Received for publication, February 13, 2003 , and in revised form, March 31, 2003.

^* Research in the laboratory of G. E. T. was supported by National Institutes of Health Grant CA76409, the Human Frontier Science Program, and the Aids for Cancer Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ A scholar of the Leukemia and Lymphoma Society. To whom correspondence should be addressed: Dept. of Microbiology, Boston University, School of Medicine, 706 Albany St., Boston, MA 02118. Tel.: 617-638-7789; Fax: 617-638-4286; E-mail: taccioli{at}bu.edu.

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