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Sunday June 16, 2002 10:25 PM GMT


Telomerase adds nucleotides to the ends of chromosomes to compensate for losses during DNA replication.


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Telomerase is an enzyme that adds hexameric TTAGGG nucleotide repeats to the ends of vertebrate chromosomal DNAs (i.e. telomeres) to compensate for losses that occur with each round of DNA replication. It is a ribonuclear protein that synthesizes the telomeres de novo (Uchida and Otsuka, 1999).


Proliferation of normal somatic cells is associated with progressive shortening of the telomeric ends of the chromosomes that at birth comprise of 10,000 to 12,000 base pairs (bp) of tandem repeats of TTAGGG.

Because of the end replication problem, a loss of 50 to 100 bp occurs with each cell replication leaving nonreplicated DNA at the 3? end of the DNA template in the absence of compensatory mechanisms (Harley et al, 1994).

In human leukocytes, some 50 bp of telomeric DNA are lost per year of normal life (Vaziri et al, 1994), with a particularly rapid loss in the first year of life. In vitro, similar telomere shortening is seen, with 50 to 80 bp lost per population doubling in cultures of CD34+ cells (Engelhardt et al, 1997) and telomeric loss of 400 to 1,500 bp is associated with allogenieic or autologous stem cell transplantation (Notaro et al, 1997). When cells achieve a critical degree of telomere shortening, they enter proliferative senescence and fail to divide further or undergo apoptosis. This has been called the Hayflick limit (Hayflick et al, 1961)

Telomerase activity is closely linked to attainment of cellular immortality, a step in carcinogenesis, while lack of such activity contributes to cellular senescence. Telomerase is activated in more than 85% of malignant tumors and enables them to maintain telomere stability (Harley et al, 1994 and Landsdrop, 1995).

However, with the exception of some self-renewing tissues with high regenerative potential, telomerase activity is usually repressed in normal somatic tissues.

Cells can escape from senescence and ?crisis? by undergoing mutational events leading to the upregulation of ribonucleoprotein telomerase, which can elongate telomeric ends. Acting in concert with oncogenes or mutated tumor suppressor genes, telomerase expression is associated with the malignant phenotype and is found in 85% to 90% of all human cancers (Holt et al, 1996). It is also expressed normally at high levels in testes and ovaries, where it is required to maintain the telomeric integrity of the germline. It is induced in T and B lymphocytes on antigen or mitogen stimulation and is constitutively expressed in the thymus and germinal centers.

Activity in normal hematopoiesis

In contrast to most somatic cells, primitive hematopoietic cells have recently been shown to exhibit low levels of telomerase activity. This low level of activity is sufficient to reduce although not completely prevent telomere loss (Vaziri et al, 1994; Harley et al, 1990; Allsopp et al, 1992). This results in expansion of the proliferative life span of hematopoietic cells. Strong telomerase activity is found in progenitor stem cells and activated lymphocytes in vitro as well as in vivo, indicating that cells with high growth requirements can readily upregulate telomerase.

Within the hemopoetic system, telomerase is expressed in proliferating CD34+ cells of progenitor (CD38+) and stem cell-enriched (CD38-) subsets, and it is rapidly induced within 24 to 48 hours of exposure of noncycling CD34+ cells to cytokines (Engelhardt et al, 1997). Studies have also shown that telomerase is repressed in quiescent stem cells (CD34+, CD38-), is activated on cell proliferation, expansion, cell cycle entry, and progression into the progenitor compartment (CD34+ / CD38+), and is repressed again on terminal cell differentiation (CD34-) (Engelhardt et al, 1997).

Paradoxically, progressive telomere shortening is observed in proliferating CD34+ cells that are expressing telomerase, suggesting that levels of enzymatic activity are insufficient to totally protect the cells from telomere erosion or that some other mechanisms, possibly involving telomere binding proteins, may inhibit enzyme action.

Excessive hematopoietic proliferation associated with repeated cycles of myelosuppressive chemotherapy and stem cell damage or with stem cell transplantation may lead to accelerated telomere shortening (Notaro et al, 1997 and Engelhardt et al, 1998). This may predispose to cytogenetic instability and aneyploidy, which characterizes myelodysplastic syndrome and secondary leukemia seen at greatly increased frequency as a complication of therapy of patients with malignant lymphoma, multiple myeloma and aplastic anemia.

Activity in leukemia

In malignant hematopoietic disorders telomerase activity is a general finding with large differences in activity levels. The strongest telomerase expression has been shown in acute leukemias and non-Hodgkin?s lymphomas, especially high grade cases. There are indications that the level of activity might parallel tumor progression and be of prognostic relevance (Yamada, 1996; Werda and Scotnicki, 1999).

In AML, accelerated phase (AP) and blastic phase (BP)-CML, basal telomerase activity was 10- to 50-fold higher than normal in one study. 

The hTERT expression level was strongly associated with telomerase activity (P=0.0001), indicating that the expression level of the catalytic subunit (hTERT) regulates telomerase activity in human acute leukemia cells. TRF1 expression, which is believed to control telomere length, was significantly elevated in patients with acute lymphoblastic leukemia (ALL) (P=0.0232) compared to those in acute myeloid leukemia (AML); TRF1 expression tended to be higher in patients without telomere shortening (P=0.077) and in those with hTERT expression (P=0.055) (Ohyashiki et al, 2001). This indicates that TRF1 may act to monitor telomere length under the condition of up-regulated telomerase activity in some neoplastic cells. In contrast, TRF2 expression in acute leukemia did not show any correlation with telomere parameters in this study (Ohyashiki et al 2001).

It is known that any deregulation of apoptosis or an escape from cellular senescence will drive the cells to neoplasia. This prompted a study to find out whether there is a direct linkage between apoptosis and telomerase activity particularly in transformed cell lines.

Telomerase activity was not found to be related to apoptosis in leukemic cell lines (Zhang et al, 2000).

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