Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals

Here we show a correlation between telomere length and organismal sensitivi ty to ionizing radiation (IR) in mammals. In particular, fifth generation ( G5) mouse telomerase RNA (mTR)(-/-) mice, with telomeres 40% shorter than i n wild-type mice, are hypersensitive to cumulative doses of gamma rays. 60% of the irradiated G5 mTR(-/-) mice die of acute radiation toxicity in the gastrointestinal tract, lymphoid organs, and kidney. The affected G5 mTR(-/ -) mice show higher chromosomal damage and greater apoptosis than similarly irradiated wildtype controls. Furthermore, we show that G5 mTR(-/-) mice s how normal frequencies of sister chromatid exchange and normal V(D)J recomb ination, suggesting that short telomeres do not significantly affect the ef ficiency of DNA double strand break repair in mammals. The IR-sensitive phe notype of G5 mTR(-/-) mice suggests that telomere function is one of the de terminants of radiation sensitivity of whole animals.