A role for the HOXB7 homeodomain protein in DNA repair.
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.
Rubin
Ethel
E
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Wu
Xinyan
X
Zhu
Tao
T
Cheung
Joyce C Y
JC
Chen
Hexin
H
Lorincz
Annaka
A
Pandita
Raj K
RK
Sharma
Girdhar G
GG
Ha
Hyo Chol
HC
Gasson
Judith
J
Hanakahi
Les A
LA
Pandita
Tej K
TK
Sukumar
Saraswati
S
D000595:Amino Acid Sequence; D034961:Antigens, Nuclear / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000072200:Ku Autoantigen; D008969:Molecular Sequence Data; D011836:Radiation Tolerance / Q000502:physiology
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; D051747:DNA-Activated Protein Kinase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen