Document Detail

The lethality of Ku86 (XRCC5) loss-of-function mutations in human cells is independent of p53 (TP53).
MedLine Citation:
PMID:  17214517     Owner:  NLM     Status:  MEDLINE    
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.
Goutam Ghosh; Gang Li; Kyungjae Myung; Eric A Hendrickson
Related Documents :
7926757 - Differential disruption of genomic integrity and cell cycle regulation in normal human ...
10388527 - Differential responses of proliferating versus quiescent cells to adriamycin.
14961077 - P53 disruption profoundly alters the response of human glioblastoma cells to dna topois...
19956847 - Icam-3 enhances the migratory and invasive potential of human non-small cell lung cance...
24552177 - Tuning cell autophagy by diversifying carbon nanotube's surface chemistry.
8906587 - Contribution of phosphoinositides and phosphatidylcholines to the production of phospha...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Radiation research     Volume:  167     ISSN:  0033-7587     ISO Abbreviation:  Radiat. Res.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-11     Completed Date:  2007-02-15     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  0401245     Medline TA:  Radiat Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  66-79     Citation Subset:  IM; S    
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Cell Proliferation
DNA Damage
DNA Helicases / biosynthesis*,  genetics*
DNA, Complementary / metabolism
DNA-Activated Protein Kinase / metabolism
Gene Expression Regulation*
Genetic Vectors
Histones / metabolism
Models, Genetic
Nuclear Proteins / metabolism
Radiation Tolerance
Radiation, Ionizing
Tumor Suppressor Protein p53 / biosynthesis*,  genetics*
Grant Support
Reg. No./Substance:
0/DNA, Complementary; 0/Histones; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p53; 0/XRCC5 protein, human; EC Protein Kinase; EC protein, human; EC 3.6.1.-/DNA Helicases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Evidence that individual variations in TP53 and CDKN1A protein responsiveness are related to inheren...
Next Document:  Initial yields of DNA double-strand breaks and DNA Fragmentation patterns depend on linear energy tr...