Telomerase extracurricular activities

S Chang, RA DePinho - Proceedings of the National …, 2002 - National Acad Sciences
S Chang, RA DePinho
Proceedings of the National Academy of Sciences, 2002National Acad Sciences
The extended growth potential of can-cer cells is critically dependent upon the maintenance
of functional telomeres, G-rich repeat sequences that cap the ends of most eukaryotic
chromosomes and serve to protect natural DNA ends from being recognized as double-
stranded breaks (reviewed in ref. 1). The inability of DNA polymerase to synthesize fully the
terminal ends of the lagging strand leads to progressive telomere shortening with each
round of cell division. The gradual erosion of telomeres to a critically short length elicits the …
The extended growth potential of can-cer cells is critically dependent upon the maintenance of functional telomeres, G-rich repeat sequences that cap the ends of most eukaryotic chromosomes and serve to protect natural DNA ends from being recognized as double-stranded breaks (reviewed in ref. 1). The inability of DNA polymerase to synthesize fully the terminal ends of the lagging strand leads to progressive telomere shortening with each round of cell division. The gradual erosion of telomeres to a critically short length elicits the successive cellular responses of senescence and crisis; each has been shown to represent formidable barriers to continued cell growth in culture (2, 3). These cell culture-based studies also seeded the view that long-term cancer cell growth and survival requires activation of one of two known mechanisms of telomere maintenance. The first and most common mechanism involves reactivation of the enzyme telomerase (4), a specialized ribonucleoprotein complex that contains a complementary RNA template (TERC) and a reverse transcriptase catalytic subunit (TERT). In telomerase reactivation, transcriptional up-regulation of the TERT gene is often the limiting event (5, 6), although TERT activity can be controlled on multiple posttranscriptional and posttranslational levels (7). The second telomere maintenance mechanism, encountered in only a minority of cancer cells, involves a telomerase-independent process termed ALT (for alternative lengthening of telomeres), which is, perhaps, mediated by the homologous recombination pathway (8, 9). The consistent presence of either mechanism in advanced human cancers has supported the assumption that the key, and perhaps only, factor in the promotion of full malignant transformation is adequate telomere reserves, and that the particular telomere maintenance mechanism used was less relevant. In this issue of PNAS, Stewart et al.(10) force a re-evaluation of this commonly held view with a provocative set of experiments showing that the actions of TERT in tumor progression extend beyond the singular role of telomere maintenance, and that TERT-mediated vs. ALT-mediated telomere maintenance are not functionally equivalent in promoting tumorigenesis. A large body of work in human cell culture models has documented the biological and genomic consequences of telomere attrition and their relationship to the suppression or promotion of cancer. Replicative senescence (also termed the Hayflick limit or Mortality Stage I) is the first cellular response elicited by passageinduced telomere attrition, and its induction requires intact p53 and RB tumorsuppressor pathways (11, 12). Inactivation of these key tumor-suppressor pathways permits extended replicative potential but also continued telomere erosion and eventual loss of telomere capping function. Uncapped telomeres are highly recombinogenic, resulting in the formation of dicentric chromosomes and breakage at the time of cell division; they also fuel high degrees of genomic instability and loss of cell viability, a period aptly termed ‘‘crisis’’(2). It is well established that only rare (1 10 7 to 1 10 5) cultured cells emerge from crisis (13, 14), and that enforced hTERT expression and, hence, telomerase activity, can avert both senescence and crisis in primary culture cells (15, 16). Importantly, hTERT expression enables full malignant transformation of primary human cells by small and large T antigen and activated H-RAS (17). Together, these studies have underscored the essential role of telomere maintenance in sustaining the proliferation of normal and neoplastic cells.
National Acad Sciences