Human telomerase and its regulation

Abstract

The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.

FIG. 1.

End replication problem. DNA replication by the conventional polymerase proceeds in the 5′-to-3′ direction. The newly synthesized leading strands would not generate overhangs, but the newly synthesized lagging strands would lose their extreme 3′ end after RNA primers are removed. In addition, both parental strands might also be subject to nuclease processing.

FIG. 2.

Two-step hypothesis of cellular senescence and immortalization. Unlike germ cells, in which telomere length is maintained by telomerase, most human somatic cells have lower levels of telomerase or are telomerase negative and experience telomere shortening with each cell division. Pluripotent stem cells are telomerase positive but do not maintain full telomere length. Telomere length shortens in stem cells at rates slower than that of telomerase-negative somatic cells. Critically shortened telomeres may signal cells to enter senescence at the Hayflick limit, or M1. This proliferative checkpoint can be overcome by inactivation of pRB/p16 or p53. Such cells continue to suffer telomere erosion and ultimately enter crisis, or M2, characterized by widespread cell death. Rare surviving cells acquire unlimited proliferative potential and stabilization of telomere length, almost universally by activation of telomerase. When cells are cultured in adequate conditions, ectopic expression of hTERT allows cells to bypass proliferation barriers and become immortal.

FIG. 3.

Gene organization of the hTERT gene. The human hTERT gene consists of 16 exons and 15 introns located on the short arm of chromosome 5 (5p15.33), approximately 2 Mb away from the telomere. It is transcribed towards the centromere. The specific telomerase domain (T domain), reverse transcriptase domain (RT domain), and the C-terminal region of the hTERT protein are indicated.