Mm. Ouellette et al., Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase, J BIOL CHEM, 275(14), 2000, pp. 10072-10076
Human fibroblasts expressing the catalytic component of human telomerase (h
TERT) have been followed for 250-400 population doublings, As expected, tel
omerase activity declined in long term culture of stable transfectants, Sup
prisingly, however, clones with average telomere lengths several kilobases
shorter than those of senescent parental cells continued to proliferate. Al
though the longest telomeres shortened, the size of the shortest telomeres
was maintained. Cells with subsenescent telomere lengths proliferated for a
n additional 20 doublings after inhibiting telomerase activity with a domin
ant-negative hTERT mutant. These results indicate that, under conditions of
limiting telomerase activity, cis-acting signals may recruit telomerase to
act on the shortest telomeres, argue against the hypothesis that the morta
lity stage 1 mechanism of cellular senescence is regulated by telomere posi
tional effects (in which subtelomeric loci silenced by long telomeres are e
xpressed when telomeres become short), and suggest that catalytically activ
e telomerase is not required to provide a protein-capping role at the end o
f very short telomeres.