Ornithine Decarboxylase Antizyme Upregulates DNA-Dependent Protein Kinase and Enhances the Nonhomologous End-Joining Repair of DNA Double-Strand Breaks in Human Oral Cancer Cells

Ornithine decarboxylase (ODC) antizyme targets ODC for ubiquitin-independent proteosome degradation, thereby inhibiting polyamine synthesis. It has been shown to regulate DNA methylation and has tumor suppressor activity. Increasing evidence suggested that antizyme may also have ODC-independent func...

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Bibliographic Details
Published in:Biochemistry (Easton) 2007-08, Vol.46 (31), p.8920-8932
Main Authors: Tsuji, Takanori, Katsurano, Miki, Ibaragi, Soichiro, Shima, Kaori, Sasaki, Akira, Hu, Guo-fu
Format: Article
Language:English
Subjects:
Antigens, Nuclear - genetics
Antigens, Nuclear - metabolism
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Cadherins - genetics
Cadherins - metabolism
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line
Cell Line, Tumor
Cell Nucleus - genetics
Cell Nucleus - metabolism
Decitabine
DNA Breaks, Double-Stranded
DNA Repair
DNA-Activated Protein Kinase - genetics
DNA-Activated Protein Kinase - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
G1 Phase - genetics
Gamma Rays
Gene Expression Profiling
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - radiation effects
Histones - genetics
Histones - metabolism
Humans
Keratinocytes - metabolism
Ku Autoantigen
Mouth Neoplasms - genetics
Mouth Neoplasms - metabolism
Mouth Neoplasms - pathology
Proteins - genetics
Proteins - metabolism
Transfection
Up-Regulation - drug effects
Up-Regulation - radiation effects
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Summary:Ornithine decarboxylase (ODC) antizyme targets ODC for ubiquitin-independent proteosome degradation, thereby inhibiting polyamine synthesis. It has been shown to regulate DNA methylation and has tumor suppressor activity. Increasing evidence suggested that antizyme may also have ODC-independent functions. Here, we report that antizyme plays a role in DNA double-strand break repairs. A zinc-inducible human antizyme gene expression vector was transfected into UM1 human oral squamous cancer cells that do not express endogenous antizyme. The resultant upregulated genes were screened by cDNA arrays and confirmed by quantitative real-time polymerase chain reaction. DNA-dependent protein kinase including its catalytic subunit DNA−PKcs and regulatory subunit Ku70, two key proteins of the DNA damage repair machinery, was significantly upregulated after ectopic expression of antizyme. Consistently, we found that UM1 cells are sensitive to γ irradiation and deficient in DNA damage repairs, as shown by radio-sensitivity and Comet assays. Ectopic expression of antizyme increased radio-resistance of UM1 cells and restored their capacity of DNA damage repairs to the level of UM2 cells that have an identical genetic background but express endogenous antizyme. Plasmid end-joining assays confirmed that antizyme enhances the ability of UM1 cells to repair DNA double-strand breaks by the nonhomologous end-joining pathway.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi7000328