Mutational analysis defines a minimum level of telomerase activity required for tumourigenic growth of human cells

Abstract

A hallmark of cancer cells is the ability to proliferate indefinitely. This acquisition of an immortal lifespan usually requires the activation of telomerase, the enzyme that elongates telomeres. Human telomerase is minimally composed of the reverse transcriptase subunit hTERT, and the RNA subunit hTR. While hTR is ubiquitously expressed in human cells, the hTERT subunit is generally transcriptionally repressed in most normal somatic cells, but is illegitimately activated to restore telomerase activity in cancer cells. Indeed, in the thousands of different human tumours assayed, 85% were scored positive for telomerase activity. However, the levels of telomerase activity detected in tumour samples can vary substantially and even some normal somatic cells have been found to have low levels of enzyme activity. As the functional significance of low levels of telomerase activity is unclear, we investigated whether there is a minimum level of telomerase activity required for tumourigenesis. Using mutants of hTERT that induce varying levels of telomerase activity, we show that there does indeed exist a threshold of activity required for the processes of immortalization, transformation and tumourigenesis. Thus, low levels of activity detected in certain somatic cells would not be expected to contribute to tumourigenesis, nor does the mere detection of telomerase in cancer cells necessarily signify an immortal lifespan.