Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation

Telomeres are specialized nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. Loss of telomere function is associa ted with rampant genetic instability and loss of cellular viability and ren ewal potential. The telomere also participates in processes of chromosomal repair, as evidenced by the 'capture' or de novo synthesis of telomere repe ats at double-stranded breaks(1-4) and by the capacity of yeast telomeres t o serve as repositories of essential components of the DNA repair machinery , particularly those involved in non-homologous end-joining(5-7) (NHEJ). He re we used the telomerase-deficient mouse. null for the essential telomeras e RNA gene (Terc). to assess the role of telomerase and telomere function o n the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernable impact on the respons e to ionizing radiation, the emergence of telomere dysfunction in late-gene ration Terc(-/-) mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt st em cells and primary thymocytes showed increased rates of apoptosis, and mo use embryonic fibroblasts (MEFs) showed diminished dose-dependent clonogeni c 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 m assive fragmentation. Our findings establish a intimate relationship betwee n functionally intact telomeres and the genomic. cellular and organismal re sponse to ionizing radiation.