Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells.

One of the most consistent differences between cancer cells and normal somatic cells is the continuous expression of telomerase, an enzyme that is important for maintenance of chromosome ends, or telomeres. It is believed that telomerase expression allows cancer cells to maintain their telomeres after many cell divisions and thereby avoid replicative senescence. We have tested this hypothesis by targeting the gene encoding the catalytic subunit of the telomerase holoenzyme, hTERT, in a human cancer cell line. Heterozygous disruption of hTERT led to a reduction in telomerase activity, telomere shortening, activation of DNA damage signaling and the appearance of a subpopulation of cells that displayed features of senescence. Targeted cells were radiosensitive, as compared with parental controls that had two intact hTERT alleles, and expressed a classical marker of senescence after irradiation. These results suggest that telomerase inhibitors might be useful in the sensitization of cancer cells to DNA damaging agents.