详细记录  
题名:Partial deficiency of DNA-PKcs increases ionizing radiation-induced mutagenesis and telomere instability in human cells
作者:Ying Zhang, Junqing Zhou, Xiaofan Cao, Qinming Zhang, Chang U.K. Lim, Robert L. Ullrich, Susan M. Bailey and Howard L. Liber
来源:Cancer Letters[IF=3.049], Volume 250, Issue 1, 18 May 2007, Pages 63-73
URL :http://dx.doi.org/10.1016/j.canlet.2006.09.021
日期:070415
摘要: Ying Zhanga, , , Junqing Zhoua, Xiaofan Caob, Qinming Zhanga, Chang U.K. Limc, Robert L. Ullricha, d, Susan M. Baileya, d and Howard L. Libera, d

aDepartment of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80521, USA
bDepartment of Statistics, Colorado State University, Fort Collins, CO 80521, USA
cCancer Center, Ordway Research Institute, Albany, New York, USA
dUniversity of Colorado Cancer Center, Denver, CO, USA

Received 1 August 2006; revised 14 September 2006; accepted 22 September 2006. Available online 13 November 2006.

Summary

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. 2.

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