Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation
| Autor: | Jayanta Chaudhuri, Geoffrey J. Gottlieb, Ronald A. DePinho, Karl Lenhard Rudolph, Lynda Chin, Shridar Ganesan, Sandy Chang, Steven E. Artandi, Chengming Zhu, Sarah R. Weiler, Kwok-Kin Wong, Frederick W. Alt |
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| Rok vydání: | 2000 |
| Předmět: |
Telomerase
Time Factors DNA Repair Genotype Cell Survival DNA repair Apoptosis Mice Transgenic DNA Fragmentation Thymus Gland Biology medicine.disease_cause Radiation Tolerance Chromosomes Mice chemistry.chemical_compound Radiation Ionizing In Situ Nick-End Labeling Genetics medicine Animals Radiosensitivity Gene Cell Nucleus Chromosome Aberrations Mutation Models Genetic Dose-Response Relationship Radiation Fibroblasts Telomere Molecular biology Cell biology Kinetics chemistry Stem cell DNA |
| Zdroj: | Nature Genetics. 26:85-88 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/79232 |
| Popis: | Telomeres are specialized nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. Loss of telomere function is associated with rampant genetic instability and loss of cellular viability and renewal potential. The telomere also participates in processes of chromosomal repair, as evidenced by the 'capture' or de novo synthesis of telomere repeats at double-stranded breaks and by the capacity of yeast telomeres to serve as repositories of essential components of the DNA repair machinery, particularly those involved in non-homologous end-joining (NHEJ). Here we used the telomerase-deficient mouse, null for the essential telomerase RNA gene (Terc), to assess the role of telomerase and telomere function on the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernable impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation Terc-/- mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts (MEFs) showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. Our findings establish a intimate relationship between functionally intact telomeres and the genomic, cellular and organismal response to ionizing radiation. |
| Databáze: | OpenAIRE |
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