Telomerase enzyme activation and human cell immortalization

Abstract

Activity of telomerase, the enzyme that synthesizes the telomere ends of linear eukaryotic chromosomes, is repressed in most normal human somatic cells but induced in most human cancers. Normal human cells that lack telomerase activity progressively lose telomere sequences. In contrast, most immortalized cell lines and malignant human tumors appear to maintain constant telomere length via telomerase activity. Telomerase is composed of at least two subunits, an RNA subunit that templates telomere synthesis, and a catalytic protein subunit. The gene encoding the catalytic protein subunit of telomerase has recently been identified, first in yeast and ciliates and then in humans. This catalytic subunit belongs to the reverse transcriptase family. Studies of telomerase subunits further define a role for telomerase in the control of mammalian cell lifespan. The expression of the human telomerase catalytic subunit gene, hTERT, is induced in immortalized cells and primary tumors. When hTERT is ectopically expressed in hitherto telomerase-negative cells, telomerase enzyme activity appears, and an extended lifespan has been observed in some cells. In contrast, disruption of the mouse telomerase RNA subunit gene, mTERC, results in a delayed failure of cell proliferation. Telomerase activity therefore appears to be necessary for the prolonged survival of mammalian cells.