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A Role for the HOXB7 Homeodomain Protein in DNA Repair

¹ Department of Oncology, Johns Hopkins University School of Medicine; ² Department of Biochemistry, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; ³ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri; ⁴ Department of Biochemistry, Georgetown University School of Medicine, Washington, District of Columbia; and ⁵ Department of Biological Chemistry, University of California, Los Angeles, California

Requests for reprints: Saraswati Sukumar, Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, Room 410, Baltimore, MD 21231-1000. Phone: 410-614-2479; Fax: 410-614-4073; E-mail: saras{at}jhmi.edu.

Homeobox genes encode transcription factors which function in body axis patterning in the developing embryo. Recent evidence suggests that the maintenance of specific HOX expression patterns is necessary for regulating the homeostasis of adult tissues as well. In this study, HOXB7 transformed human mammary epithelial cells, MCF10A, to grow in minimally supplemented medium, to form colonies in Matrigel, and display resistance to ionizing radiation. Searching for protein partners of HOXB7 that might contribute to resistance to ionizing radiation, we identified four HOXB7-binding proteins by GST pull-down/affinity chromatography and confirmed their interactions by coimmunoprecipitation in vivo. Interestingly, all four HOXB7-binding proteins shared functions as genomic caretakers and included members of the DNA-dependent protein kinase holoenzyme (Ku70, Ku80, DNA-PK_cs) responsible for DNA double-strand break repair by nonhomologous end joining pathway and poly(ADP) ribose polymerase. Exogenous and endogenous expression of HOXB7 enhanced nonhomologous end joining and DNA repair functions in vitro and in vivo, which were reversed by silencing HOXB7. This is the first mechanistic study providing definitive evidence for the involvement of any HOX protein in DNA double-strand break repair. [Cancer Res 2007;67(4):1527–35]

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