Partial deficiency of DNA-PKcs increases ionizing radiation-induced mutagenesis and telomere instability in human cells

Ying Zhang, Junqing Zhou, Xiaofan Cao, Qinming Zhang, Chang U.K. Lim, Robert L. Ullrich, Susan M. Bailey, Howard L. Liber

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The correct repair of DNA double-strand breaks (DSBs) is essential to maintaining the integrity of the genome. Misrepair of DSBs is detrimental to cells and organisms, leading to gene mutation, chromosomal aberration, and cancer development. Nonhomologous end-joining (NHEJ) is one of the principal rejoining processes in most higher eukaryotic cells. NHEJ is facilitated by DNA-dependent protein kinase (DNA-PK), which is composed of a catalytic subunit, DNA-PKcs, and the heterodimeric DNA binding regulatory complex Ku70/86. Null mutation of DNA-PKcs leads to immunodeficiency, chromosomal aberration, gene mutation, telomeric end-capping failure, and cancer predisposition in animals and cells. However, it is unknown whether partial deficiency of DNA-PKcs as might occur in a fraction of the population (e.g., heterozygotes), influences cellular function. Using small interfering RNA (siRNA) transfection, we established partial deficiency of DNA-PKcs in human cells, ranging from 4 to 85% of control levels. Our results reveal for the first time, that partial deficiency of DNA-PKcs leads to increased ionizing radiation (IR)-induced mutagenesis, cell killing, and telomere dysfunction. Radiation mutagenesis was increased inversely with DNA-PKcs protein level, with the most pronounced effect being observed in cells with protein levels below 50% of controls. A small but statistically significant increase in IR-induced cell killing was observed as DNA-PKcs levels decreased, over the entire range of protein levels. Frequencies of IR-induced telomere-DSB fusion was increased at levels of DNA-PKcs as low as ∼50%, similar to what would be expected in heterozygous individuals. Taken together, our results suggest that even partial deficiency of DNA repair proteins may represent a considerable risk to genomic stability.

Original languageEnglish (US)
Pages (from-to)63-73
Number of pages11
JournalCancer Letters
Volume250
Issue number1
DOIs
StatePublished - May 18 2007

Keywords

  • DNA-PKcs
  • Ionizing radiation
  • Mutagenesis
  • Partial deficiency
  • Telomere

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhang, Y., Zhou, J., Cao, X., Zhang, Q., Lim, C. U. K., Ullrich, R. L., Bailey, S. M., & Liber, H. L. (2007). Partial deficiency of DNA-PKcs increases ionizing radiation-induced mutagenesis and telomere instability in human cells. Cancer Letters, 250(1), 63-73. https://doi.org/10.1016/j.canlet.2006.09.021