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Departments of ¹ Pharmacology and Toxicology and ² Radiation Oncology, ³ Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; ⁴ Division of Life Sciences, Department of Molecular Biology, Lawrence Berkeley Laboratory, Berkeley, California; and ⁵ Howard Hughes Medical Institute, Section of Immunology, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Lawrence F. Povirk, Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980230, Richmond, VA 23298. Phone: 804-828-9640; Fax: 804-828-8079. E-mail: lpovirk{at}gems.vcu.edu

Incomplete DNA repair or misrepair can contribute to the cytotoxicity of DNA double-strand breaks. Consequently, interference with double-strand break repair, by pharmacologic or genetic means, is likely to sensitize tumor cells to ionizing radiation. The current studies were designed to inhibit the nonhomologous end joining repair pathway by interfering with the function of the XRCC4/ligase IV complex. A PCR-generated fragment of the XRCC4 gene, encompassing the homodimerization and ligase IV–binding domains, was inserted into a plasmid vector (pFLAG-CMV-2) expressing the FLAG peptide and the cassette encoding FLAG-tagged XRCC4 fragment was cloned into an adenoviral vector. Both the plasmid and the corresponding adenovirus elicited robust expression of a truncated XRCC4 protein designed to compete in a dominant-negative fashion with full-length XRCC4 for binding to ligase IV. Binding of the XRCC4 fragment to ligase IV in vivo was confirmed by immunoprecipitation. Clonogenic survival assays showed that the adenovirus expressing the truncated XRCC4 protein sensitizes MDA-MB-231 breast tumor cells to ionizing radiation, presumably through interference with the functional activity of ligase IV, leading to inhibition of the final ligation step in end joining. These studies support the potential clinical utility of combining radiation therapy with agents that inhibit DNA double-strand break repair.

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.

Note: D.G. Schatz is an investigator of the Howard Hughes Medical Institute.

Received 6/13/05; revised 7/13/05; accepted 7/25/05.

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