Differential etoposide sensitivity of cells deficient in the Ku and DNA- PKcs components of the DNA-dependent protein kinase
| Autor: | D. T. Weaver, S. Inoue, Shengfang Jin |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
G2 Phase
Cancer Research Ku80 DNA Repair DNA repair DNA-Activated Protein Kinase Mice SCID Protein Serine-Threonine Kinases Cell Line Cell cycle phase Mice Cricetinae medicine Animals Ku Autoantigen DNA-PKcs Etoposide Ku70 biology Topoisomerase DNA Helicases Nuclear Proteins Antigens Nuclear General Medicine Cell cycle Antineoplastic Agents Phytogenic Molecular biology DNA-Binding Proteins biology.protein Dimerization DNA Damage Protein Binding medicine.drug |
| Zdroj: | Carcinogenesis. 19:965-971 |
| ISSN: | 1460-2180 |
| DOI: | 10.1093/carcin/19.6.965 |
| Popis: | Etoposides block cell division by interfering with the action of topoisomerase II, leaving enzyme-DNA double-strand breaks. We found that certain components of the trimeric DNA-dependent protein kinase influence cell survival following etoposide damage. Interestingly, either Ku70- or Ku80-deficient cell lines, but not mutant cell lines of the DNA-PK catalytic sub-unit (DNA-PKcs), were found to be hypersensitive to the effects of etoposide VP16. Ku70- and Ku80-deficient cells can be complemented to an etoposide resistant phenotype by introducing wildtype Ku70 or Ku80 cDNAs. Mutational analysis of introduced Ku70 cDNAs into murine embryonic stem cells deleted for Ku70 (‐/‐) showed that mutants where heterodimerization and DNA binding functions of Ku were disrupted, also blocked the restoration of etoposide resistance. In contrast with the differential etoposide sensitivity of DNA-PK mutants, both Ku- and DNA-PKcs-deficient cell lines showed G 2 ionizing radiation-induced delays, a cell cycle phase where topoisomerase II function is critical. Thus, the topoisomerase II cleaved complexes may be an example of DNA lesions requiring the Ku heterodimer, but not DNA-PK for DNA repair. |
| Databáze: | OpenAIRE |
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