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Human telomeres function as a protective structure capping both ends of the chromosome. They are composed of long, repetitive sequences of TTAGGG, associated with a variety of telomere-binding proteins. Telomeres protect the chromosomes from end-to-end fusion, recombination, and degradation, all events that can lead to cell death. At cell replication, telomeres cannot be completely replicated. They are gradually shortened, and when the telomeres reach a critical threshold, cell replication is arrested in what is called “replicative senescence.” Thus, telomeres act as an intrinsic “counting” mechanism of the cell’s aging process. Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is almost absent in somatic cells, but it is detected in embryonic stem cells and in the vast majority of tumor cells. Tumor cells, in fact, may contain short and stable telomeres that confer immortality to the cancer cells, which are thus able to replicate indefinitely. The deregulation of telomeres thus plays an important role in the relationship between premature aging syndrome and cancer. This review describes the recent advances in the molecular characterization of telomeres, the regulation of telomerase activity in cancer pathogenesis, and the potential of targeting telomerase for cancer therapy.

In the early 1930s, Hermann J. Muller and Barbara McClintock described the telomere (from the Greek word “telos,” meaning end, and “meros,” meaning part) as a protective structure at the terminal end of the chromosome. When this structure is absent, end-to-end fusion of the chromosome may occur, with ensuing cell death. In the 1970s, James D. Watson described what he called “end-replication problems.” During DNA replication, DNA-dependent DNA polymerase does not completely replicate the extreme 5′ terminal end of the chromosome, leaving a small region of telomere uncopied. He noted that a compensatory mechanism was needed to fill this terminal gap in the chromosome, unless the telomere was shortened with each successive cell division.

Meanwhile in the 1960s, Hayflick described a biological view of aging. He found that human diploid cells proliferate a limited number of times in a cell culture. The “Hayflick limit” is the maximal number of divisions that a cell can achieve in vitro. When cells reach this limit, they undergo morphologic and biochemical changes that eventually lead to arrest of cell proliferation, a process called “cell senescence”

Then in the 1970s, Olovnikov connected cell senescence with end-replication problems in his “Theory of Marginotomy,” in which telomere shortening was proposed as an intrinsic clocklike mechanism of aging that tracks the number of cell divisions before the arrest of cell growth or replicative senescence sets in. Greider and colleagues, in 1988, corroborated this theory when they observed a progressive loss in telomere length in dividing cells cultured in vitro.

In 1978, Elizabeth Blackburn found that the molecular structure of telomeres in Tetrahymena pyriformis contains long repeating units rich in thymine (T) and guanine (G) residues. In 1984, she and her colleagues isolated telomerase, the enzyme responsible for the maintenance and elongation of telomere length. In 1989, Gregg reported the existence of telomerase activity in human cancer cell lines, which was thought to contribute to the immortality of tumor cells. At about the same time, Greider and associates found that telomerase was nearly always absent in normal somatic cells.

In the 1990s, Shay and Harley detected telomerase in 90 of 101 human tumor cell samples (from 12 different tumor types), but found no activity in 50 normal somatic cell samples (from 4 different tissue types). Since then, more than 2600 human tumor samples have been examined and telomerase activity detected in about 90% of all tumor cells. The obvious implication is that telomerase may play a major role in the pathogenesis of cancer.

Because of their role in physiologic aging, cancer pathogenesis, and premature aging syndromes (eg, progeria), telomeres and telomerase are currently under intensive investigation. This review focuses on the molecular structure of telomeres, telomerase and associating proteins, the role of telomere shortening, the activation of telomerase in cancer pathogenesis, and the potential of targeting telomerase for cancer therapy.