Erosion of the telomeric single-strand overhang at replicative senescence.

Cultured primary human cells inevitably enter a state of replicative senescence for which the specific molecular trigger is unknown. We show that the single-strand telomeric overhang, a key component of telomere structure, is eroded at senescence. Expression of telomerase prevents overhang loss, suggesting that this enzyme prevents senescence by maintaining proper telomere structure.

Telomerase contributes to tumorigenesis by a telomere length-independent mechanism.

Once immortalized, human cells are susceptible to transformation by introduction of an oncogene such as ras. Several lines of evidence now suggest that the maintenance of telomere length is a major determinant of replicative lifespan in human cells and thus of the immortalized state. The majority of human tumor cells acquire immortality through expression of the catalytic subunit of telomerase (hTERT), whereas others activate an alternative mechanism of telomere maintenance (ALT) that does not depend on the actions of telomerase.