Iron chelators reduce chromosomal breaks in ataxia-telangiectasia cells
| Autor: | Rodney E. Shackelford, Torrie C. Brooks, Suming Wang, Mary Lowery-Nordberg, Yumei Fu, Adrian Sequeira, Ryan P. Manuszak, Anping Chen |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Genome instability
Antioxidant Iron Recombinant Fusion Proteins medicine.medical_treatment Cell Cell Culture Techniques Cell Cycle Proteins Transferrin receptor Ataxia Telangiectasia Mutated Proteins Deferoxamine Protein Serine-Threonine Kinases Biology Iron Chelating Agents Biochemistry Antibodies Catechin Cell Line law.invention Ataxia Telangiectasia chemistry.chemical_compound tert-Butylhydroperoxide law Receptors Transferrin Organometallic Compounds medicine Humans Molecular Biology Thioctic Acid Tumor Suppressor Proteins Chromosome Breakage Drug Synergism Cell Biology medicine.disease Molecular biology Salicylates DNA-Binding Proteins medicine.anatomical_structure chemistry Ataxia-telangiectasia biology.protein Recombinant DNA Antibody DNA Mutagens |
| Zdroj: | DNA Repair. 5:1327-1336 |
| ISSN: | 1568-7864 |
| DOI: | 10.1016/j.dnarep.2006.05.041 |
| Popis: | Ataxia-telangiectasia (A-T) is characterized by ataxia, genomic instability, and increased cancer incidence. Previously, iron chelator concentrations which suppressed normal cell colony formation increased A-T cell colony formation. Similarly, iron chelators preferentially increased A-T cell colony formation following peroxide exposure compared to normal cells. Last, A-T cells exhibited increased short-term sensitivity to labile iron exposure compared to normal cells, an event corrected by recombinant ATM (rATM) expression. Since chromosomal damage is important in A-T pathology and iron chelators exert beneficial effects on A-T cells, we hypothesized that iron chelators would reduce A-T cell chromosomal breaks. We treated A-T, normal, and A-T cells expressing rATM with labile iron, iron chelators, antioxidants, and t-butyl hydroperoxide, and examined chromosomal breaks and ATM activation. Additionally, the effect of ATM-deficiency on transferrin receptor (TfR) expression and TfR activity blockage in A-T and syngeneic A-T cells expressing rATM was examined. We report that (1) iron chelators and iron-free media reduce spontaneous and t-butyl hydroperoxide-induced chromosomal breaks in A-T, but not normal, or A-T cells expressing rATM; (2) labile iron exposure induces A-T cell chromosomal breaks, an event lessened with rATM expression; (3) desferal, labile iron, and copper activate ATM; (4) A-T cell TfR expression is lowered with rATM expression and (5) blocking TfR activity with anti-TfR antibodies increases A-T cell colony formation, while lowering chromosomal breaks. ATM therefore functions in iron responses and the maintenance of genomic stability following labile iron exposure. |
| Databáze: | OpenAIRE |
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