| The lethality of Ku86 (XRCC5) loss-of-function mutations in human cells is independent of p53 (TP53). | |
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MedLine Citation:
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PMID: 17214517 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Ku86 is one of the two regulatory subunits of the DNA-PK (DNA-dependent protein kinase) complex that is required for DNA double-strand break repair in mammalian cells. In a previous study, by means of somatic gene targeting, we generated human cell lines deficient in Ku86 (XRCC5). Heterozygous human Ku86 cells exhibited a wide array of haploinsufficient phenotypes, including sensitivity to ionizing radiation, defects in DNA-PK and DNA end-binding activities, elevated levels of p53 (TP53) and gamma-H2AX foci, and a defect in cell proliferation with an increase in the frequency of aneuploid cells. Here we demonstrate that the overexpression of a human Ku86 cDNA complemented the deficiencies of these cells to wild-type levels. In contrast, Ku86 overexpression only partially rescued the telomere defects characteristic of Ku86 heterozygous cells and did not rescue their genetic instability. Additionally, in stark contrast to every other species described to date, we had shown earlier that homozygous human Ku86(-/-) cells are inviable, because they undergo 8 to 10 rounds of cell division before succumbing to apoptosis. The tumor suppressor protein p53 regulates the DNA damage response in mammalian cells and triggers apoptosis in the face of excessive DNA damage. Correspondingly, ablation of p53 expression has repeatedly been shown to significantly ameliorate the pathological effects of loss-of-function mutations for a large number of DNA repair genes. Surprisingly, however, even in a p53-null genetic background, the absence of Ku86 proved lethal. Thus the gene encoding Ku86 (XRCC5) is an essential gene in human somatic cells, and its absence cannot be suppressed by the loss of p53 function. These results suggest that Ku86 performs an essential role in telomere maintenance in human cells. |
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Authors:
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Goutam Ghosh; Gang Li; Kyungjae Myung; Eric A Hendrickson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Radiation research Volume: 167 ISSN: 0033-7587 ISO Abbreviation: Radiat. Res. Publication Date: 2007 Jan |
Date Detail:
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Created Date: 2007-01-11 Completed Date: 2007-02-15 Revised Date: 2012-06-25 |
Medline Journal Info:
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Nlm Unique ID: 0401245 Medline TA: Radiat Res Country: United States |
Other Details:
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Languages: eng Pagination: 66-79 Citation Subset: IM; S |
Affiliation:
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Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Proliferation DNA Damage DNA Helicases / biosynthesis*, genetics* DNA, Complementary / metabolism DNA-Activated Protein Kinase / metabolism Gene Expression Regulation* Genetic Vectors Heterozygote Histones / metabolism Humans Models, Genetic Mutation* Nuclear Proteins / metabolism Radiation Tolerance Radiation, Ionizing Tumor Suppressor Protein p53 / biosynthesis*, genetics* |
| Grant Support | |
ID/Acronym/Agency:
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GM069576/GM/NIGMS NIH HHS; HL079559/HL/NHLBI NIH HHS; P30 CA077598-09/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA, Complementary; 0/Histones; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p53; 0/XRCC5 protein, human; EC 2.7.11.1/DNA-Activated Protein Kinase; EC 2.7.11.1/PRKDC protein, human; EC 3.6.1.-/DNA Helicases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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