Telomerase

Telomerase, enzyme that influences cell life span by adding organic compounds known as nucleotides to telomeres, segments of DNA located at the ends of chromosomes. Telomeres consist of repetitive DNA sequences wherein the number of repeats determines the maximum life span of a cell. For context, some human cells have 1,500 to 2,000 such repeats at the end of each chromosome; the repeat sequence in humans and other mammals is TTAGGG (T, A, and G are the bases thymine, adenine, and guanine).

Telomerase was discovered in 1984 by American scientists Elizabeth H. Blackburn and Carol W. Greider, who shared with Jack W. Szostak the 2009 Nobel Prize for Physiology or Medicine for their research on telomeres and mechanisms of chromosome maintenance. In particular, the researchers found that telomerase, which Blackburn and Greider initially referred to as terminal transferase, plays a critical role in preserving cell life span.

Characteristics

Telomerase is classified as a ribonucleoprotein. It consists of a ribonucleic acid (RNA), generally known as the telomerase RNA, and a catalytic protein subunit, known as telomerase reverse transcriptase (TERT). It also contains various accessory proteins that are unique to each species. The structural elements of telomerase are arranged in such a way that the enzyme essentially wraps around the end of the chromosome as it attaches complementary repeat sequences.

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Telomerase is constantly active only in certain types of cells. For example, in germ cells (reproductive cells that give rise to sperm and egg cells), ongoing telomerase activity allows the cells to retain their full chromosome length in preparation for sexual reproduction and the transmission of genes to offspring. In embryonic tissues, telomerase elongates telomeres to a set length, which determines cell life span. As embryonic tissues differentiate and mature, telomerase activity diminishes.

The ability of telomerase to impart immortality to cells is a prominent feature of most cancer cells. In cells undergoing malignant transformation (progression to cancer), telomeres continue to shorten. However, as the crisis point nears (the point at which the cell is prevented from dividing further due to shortened length), the formerly quiescent telomerase enzyme becomes activated, mainly through gene mutation or genomic rearrangement. The resulting aberrant telomerase activity prevents the further reduction of telomere length, thereby increasing the longevity of cancer cells and facilitating their unregulated replication.

Mechanism

In eukaryotic organisms (in which cells contain a clearly defined nucleus), each time a cell replicates, telomere length shortens. This occurs because as DNA is copied, one of the two new strands—the so-called leading strand—is synthesized continuously, whereas the other—the lagging strand—is synthesized in short pieces, or Okazaki fragments. As the point of replication, or replication fork, nears the end of the chromosome, there typically is a short DNA segment on the leading strand that remains unpaired with an Okazaki fragment. This part of the sequence, referred to as an overhang, is therefore not replicated and is cleaved off the strand. Thus, with each round of cell division, the overall length of the chromosome becomes reduced.

Telomeres, which possess a complementary single-strand overhang, help prevent the loss of DNA by forming a “cap” over the end of the chromosome. Although the cap is highly protective for the chromosome, a small amount of the telomere repeat sequence still is lost with each round of replication. In germ cells, embryonic stem cells, and cancer cells, telomerase activity prevents the loss of telomere DNA by attaching repeat sequences. In doing so, telomerase extends the nucleotide sequence at the chromosome end, which enables cells to escape senescence, the process by which cells age to the point of permanently ceasing cell division, but also still remain alive.

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Telomerase in disease

Changes in telomerase levels and function are associated with certain diseases. In particular, the absence or impairment of telomerase activity can result in progressive telomere shortening, causing telomeres to prematurely reach the crisis point, inducing cell senescence or chromosomal instability, as well as cell death. Such deficiencies in telomerase often result from genetic mutation and manifest in conditions such as hepatic fibrosis, pulmonary fibrosis, and bone marrow failure and acute myeloid leukemia. Mutations in telomerase that reduce the stability of the enzyme complex or that alter its enzymatic activity can further cause organ failure. In addition, mutations in TERT, the gene that encodes telomerase, tend to result in excess telomerase production and activity. Such excesses potentially fuel cancer by enabling cancer cells to maintain their telomeres indefinitely.

In mice, reduced life span has been linked to variations in TERC (telomerase RNA component), which encodes the RNA segment of the telomerase enzyme. The variations are associated with reduced telomere length; mice who carry them also exhibit an increased likelihood of tumor development. Such observations have opened avenues for research aimed at leveraging telomerase therapeutically, both to treat relevant diseases and to reverse the cellular aging process and potentially extend life span.