Radiation sensitivity increases with proliferation-associated telomere dysfunction in nontransformed human epithelial cells.
Epidemiological studies have demonstrated age differences among human adults in susceptibility to radiation, with cancer cases attributable to radiation being more frequent for older individuals at time of exposure. In addition to the notion that susceptibility increases because of progressive decline in DNA monitoring and immunosurveillance, telomere function is now emerging as a new and important factor in modulating cellular and organism sensitivity to ionizing radiation. The link between telomeres and radiosensitivity is well-documented in humans, but the causal events remain elusive. In this paper, it is shown that irradiated human epithelial cells with short dysfunctional telomeres derived from normal mammary gland display elevated DNA damage. An approach identifying the specific chromosomes with critically shortened telomeres in each donor has allowed us to conclude that short dysfunctional telomeres in human epithelial cells join radiation-induced DNA broken ends, thus interfering with their efficient repair. These findings argue against telomeres participating as sensors or transducers of DNA damage, as previously suggested. Rather, our current findings give support to the idea that dysfunctional telomeres, by acting as an additional joining option, reduce the repair fidelity of DNA broken-ends induced by radiation throughout the genome. In the mammary gland, age-dependent telomere attrition due to epithelial turnover, together with the accretion of checkpoint deficiencies, might render the accumulation of short dysfunctional telomeres. This implies that the risks associated with mammography screening could be higher than previously assumed. Our results have the possibility of imprinting a temporal dimension onto radiation sensitivity, namely, that shortened telomeres in aged cells may more easily compromise normal tissue function in the elderly.
Soler
David
D
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Pampalona
Judit
J
Tusell
Laura
L
Genescà
Anna
A
D002460:Cell Line; D049109:Cell Proliferation / Q000528:radiation effects*; D016922:Cellular Senescence; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D015894:Genome, Human / Q000528:radiation effects; D006801:Humans; D011836:Radiation Tolerance; D016615:Telomere / Q000528:radiation effects*