Fundamental mechanisms of telomerase action in yeasts and mammals: understanding telomeres and telomerase in cancer cells

Abstract

Aberrant activation of telomerase occurs in 85-90% of all cancers and underpins the ability of cancer cells to bypass their proliferative limit, rendering them immortal. The activity of telomerase is tightly controlled at multiple levels, from transcriptional regulation of the telomerase components to holoenzyme biogenesis and recruitment to the telomere, and finally activation and processivity. However, studies using cancer cell lines and other model systems have begun to reveal features of telomeres and telomerase that are unique to cancer. This review summarizes our current knowledge on the mechanisms of telomerase recruitment and activation using insights from studies in mammals and budding and fission yeasts. Finally, we discuss the differences in telomere homeostasis between normal cells and cancer cells, which may provide a foundation for telomere/telomerase targeted cancer treatments.

Keywords: Hayflick limit; S. pombe; replicative senescence; shelterin; t-stumps; telomere length homeostasis.

Figure 1.

Shelterin conservation at the telomere from yeast to mammals. Schematic diagrams depict the proteins of the shelterin complexes and telomerase complex in (a) mammalian cells and (b) fission and (c) budding yeasts. Orthologous proteins are shaded in the same colour. Known interactions with the telomerase complexes and chromatin modifying proteins are indicated. Other interaction proteins are omitted from these diagrams.

Figure 2.

Models of telomere maintenance in normal and cancer cells. Schematic diagrams depicting two mode of telomere length homeostasis by distinct telomerase action. In normal cells (a), telomerase is recruited to the shortest telomere and it is extended until it is no longer short. Theoretically, such action would require a steady interaction between the telomere and telomerase, resulting in continuous extension. In this mode, distribution of telomere length would be the Gaussian like. In contrast, in cancer cells (b), telomerase recruitment appears to be random as it is independent of telomere length. Furthermore, telomeres are extended only a small amount, perhaps indicating an inability to maintain a steady interaction with telomerase, resulting in short extension and release. Such casual interaction permits repetitive recruitment of telomerase to new telomeres. In this mode, distribution of telomere length would be dispersal, resulting in retention of some short telomeres.