期刊
DNA REPAIR
卷 7, 期 5, 页码 762-774出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2008.02.008
关键词
NHEJ; Ku; DNA-PK; gene targeting; telomeres; human somatic cell lines
资金
- NCI NIH HHS [P30 CA077598, R01 CA154461] Funding Source: Medline
- NHLBI NIH HHS [R01 HL079559, R01 HL079559-04, HL079559] Funding Source: Medline
- NIGMS NIH HHS [R01 GM069576-04, GM069576, R01 GM069576] Funding Source: Medline
NHEJ (non-homologous end joining) is the predominant mechanism for repairing DNA double-stranded breaks in human cells. One essential NHEJ factor is the Ku. heterodimer, which is composed of Ku70 and Ku86. Here we have generated heterozygous loss-of-function mutations for each of these genes in two different human somatic cell lines, HCT116 and NALM-6, using gene targeting. Previous work had suggested that phenotypic differences might exist between the genes and/or between the cell lines. By providing a side-by-each comparison of the four cell lines, we demonstrate that there are indeed subtle differences between loss-of-function mutations for Ku70 versus Ku86, which is accentuated by whether the mutations were derived in the HCT116 or NALM-6 genetic background. Overall, however, the phenotypes of the four lines are quite similar and they provide a compelling argument for the hypothesis that Ku. loss-of-function mutations in human somatic cells result in demonstrable haploinsufficiencies. Collectively, these studies demonstrate the importance of proper biallelic expression of these genes for NHEJ and telomere maintenance and they provide insights into why these genes are uniquely essential for primates. (c) 2008 Elsevier B.V. All rights reserved.
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