DNA Damage is the Triggering Event for Apoptosis in Fanconi Anemia (FA) ♦ 748
| Autor: | Steven Arkin, Philip Risser, Jaime Goldstein, Jeffrey M. Lipton |
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| Rok vydání: | 1998 |
| Předmět: | |
| Zdroj: | Pediatric Research. 43:130-130 |
| ISSN: | 1530-0447 0031-3998 |
| DOI: | 10.1203/00006450-199804001-00769 |
| Popis: | FA is an autosomal recessive disorder associated with chromosomal instability, pancytopenia and risk of neoplasia. De novo and in the presence of DNA alkylating agents, FA cells have increased chromosome breaks, prolonged G2/M phase of the cell cycle and increased apoptosis relative to normal. Studies were performed to determine if FA cells have an intrinsically increased rate of apoptosis or whether the observed apoptosis is an appropriate cellular response following unrepaired DNA damage. FA and non-FA fibroblast cell lines exposed to varying concentrations of nitrogen mustard[NM] were studied using flow cytometry. At each [NM] the percent of cells in G2/M arrest and the percent of apoptotic cells was quantitated and threshold[NM] for increased cell cycle arrest and apoptosis were correlated. For Lesch-Nyhan and normal cells the threshold [NM] triggering increased G2/M arrest were 0.125 or 0.25 μg/ml respectively. Accumulation of apoptotic cells did not occur until these thresholds were met or exceeded. In FA cell lines the threshold [NM] triggering increased G2/M arrest and apoptosis was reduced (0.005-0.0125 μg/ml). As with non-FA cells, accumulation of apoptotic FA cells did not occur until the threshold [NM] for increased G2/M arrest was met or exceeded. These data (table) indicate that, in all cell lines tested, DNA damage, as detected using G2/M arrest as a surrogate marker, is the primary insult and that apoptosis is a cellular response to DNA damage. We conclude that the increased apoptosis detected in FA cells is an appropriate cellular response to unrepaired DNA damage rather than a primary pathophysiologic process. |
| Databáze: | OpenAIRE |
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