Telomerase finally gives up its structure

In a landmark study, researchers from the Wistar Institute have deciphered the structure of the active region of telomerase, an enzyme that plays a major role in the development of nearly all cancers. It is hoped that this achievement will open the door to the creation of new, broadly-effective cancer drugs, as well as anti-ageing therapies. The results of the work have been published in the 31st August online edition of Nature (10.1038/nature07283).

Scientists have been searching for over ten years to develop drugs that shut down telomerase, which is considered the best target for the development of new cancer treatments, but they have been hampered in large part by a lack of knowledge of the enzyme's structure. The new findings should help investigators in their efforts to design effective telomerase inhibitors. According to lead study author, Dr Emmanuel Skordalakes, assistant professor in Wistar's Gene Expression and Regulation Program: "Telomerase is an ideal target for chemotherapy because it is active in almost all human tumours, but inactive in most normal cells. That means a drug that deactivates telomerase would likely work against all cancers, with few side effects."

In humans, telomerase adds multiple repeats of a short DNA sequence to the ends of chromosomes, known as telomeres, thus preventing damage and the loss of genetic information during cell division. When telomerase is dormant, telomeres shorten each time a cell divides, eventually leading to genetic instability and cell death. The enzyme is active in cells that multiply frequently, such as embryonic stem cells, but is switched off almost entirely in normal adult cells. Cancer cells, however, often regain the ability to activate telomerase, which has been implicated in 90 per cent of human tumours. The enzyme permits cells to replicate indefinitely and achieve the cellular immortality that is the hallmark of cancer.

Telomerase is a complex structure made up of multiple protein domains and a stretch of RNA, which contains the template the enzyme uses to synthesise telomeres. In 2007, the researchers solved the structure of a key segment of the molecule, the TRBD domain, where RNA binding occurs. However, the complexity of telomerase has proved a roadblock to determining the enzyme's overall architecture, as has the ability to obtain sufficient quantities of the enzyme.

By screening a wide variety of organisms, including protozoa and insects, the scientists discovered that a gene from the red flour beetle could produce telomerase in copious amounts, and a stable form. The researchers used X-ray crystallography, to determine the 3D structure of the enzyme's active region, the catalytic component called telomerase reverse transcriptase protein (TERT). The work revealed surprising features, including the fact that the molecule's three domains are organised into a doughnut shape, an unexpected configuration. Knowledge of the structure allowed the researchers to create a model of the enzyme's function. Looking forward, the scientists plan to further study TERT and search for new telomerase inhibitors that could become cancer therapies, as well as looking at modifying existing drugs. Now telomerase has finally given up its structure, the hard work really starts.

Matthew Dennis - Editor, Cancer Drug News