Journal
NATURE GENETICS
Volume 26, Issue 1, Pages 85-88Publisher
NATURE AMERICA INC
DOI: 10.1038/79232
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Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD028317, R01HD034880] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [K08AR002104] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [K08AG001019] Funding Source: NIH RePORTER
- NIAMS NIH HHS [K08AR02104-01] Funding Source: Medline
- NIA NIH HHS [K08 AG001019] Funding Source: Medline
- NICHD NIH HHS [R01HD28317, R01HD 34880] Funding Source: Medline
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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(1-4) 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(5-7) (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.
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