Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs)

DOI Web Site 被引用文献5件
  • Erin Convery
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Euy Kyun Shin
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Qi Ding
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Wei Wang
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Pauline Douglas
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Laurie S. Davis
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Jac A. Nickoloff
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Susan P. Lees-Miller
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
  • Katheryn Meek
    Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824; ReliaGene Technologies, New Orleans, LA 70123; Departments of Biochemistry and Molecular Biology and Biological Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 74235; and Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131

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<jats:p>Two major DNA double-strand break repair pathways exist in all eukaryotes, nonhomologous DNA end joining (NHEJ) and homologous recombination (HR). Although both pathways can function throughout the cell cycle, NHEJ predominates in G<jats:sub>0</jats:sub>/G<jats:sub>1</jats:sub>(when a replicated sister chromatid is unavailable), whereas HR makes a more substantial contribution in S and G<jats:sub>2</jats:sub>. How a cell chooses between these two important DNA repair pathways is largely unknown. DNA-dependent protein kinase (DNA-PK) is critical for NHEJ. Here, we describe two conserved splice variants of a catalytic subunit of DNA-PK (DNA-PKcs) that are expressed predominately in nondividing cells. Although both encode stable products, neither reverses the NHEJ defects in DNA-PKcs-deficient cells. In fact, cells expressing one of the DNA-PKcs variants are slightly more radiosensitive than cells completely deficient in DNA-PKcs. We investigated whether cells expressing the DNA-PKcs variants had any other DNA repair deficits and found that these cells are considerably more sensitive to both etoposide and mitomycin C than cells that express no DNA-PKcs at all. Because repair of DNA damage induced by these two agents requires intact HR, we tested whether the NHEJ-defective variants of DNA-PKcs inhibit double-strand break-induced HR in an integrated substrate. In cells expressing the NHEJ-defective variants, HR was markedly reduced. Because the splice variants are expressed highly only in nondividing cells, quiescent cells would be afforded a mechanism to inhibit repair by means of HR when sister chromatids are not available as templates for accurate repair with low risk of genome rearrangement, thereby enhancing genome stability.</jats:p>

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