Published online 31 August 2008 | Nature | doi:10.1038/news.2008.1070


Heart of 'ageing enzyme' revealed

Telomerase protein structure will help research into ageing and cancer.

telomeraseThis structure of telomerase shows the molecule's protein component (in green) in complex with RNA (in beige) and DNA (in purple).Wistar Institute

The part of the enzyme that controls the timing mechanism of cellular ageing has been revealed. The X-ray crystal structure offers insights into the ageing process of normal cells, and may provide a safer method for treating up to 90% of human cancers.

Telomerase maintains the length of telomeres — the end section of chromosomes — by adding repeating sequences of DNA to them, preventing damage during each cell-division cycle, when chromosomes are shortened. The enzyme is highly expressed in embryonic stem cells, allowing them to divide repeatedly without chromosome damage, but its absence in most adult cells leads to a gradual loss of functional DNA. This is considered to be an important element in determining cell life expectancy. However, in many tumours the enzyme is reactivated, allowing the abnormal cells to continue dividing indefinitely.

Since the discovery of telomerase in 1985 by Elizabeth Blackburn1 and her colleague Carol Greider at the University of California, Berkeley, the enzyme has been recognized as an important target for developing cancer therapies. But the work has been hampered by the complexity and delicacy of the molecule, which is made up of protein and RNA.

Short solution

“This is a crucial part of the puzzle in understanding how telomerase works.”

Liz Baker
Cancer Research UK

So a team led by Emmanuel Skordalakes at the Wistar Institute in Philadelphia, Pennsylvania, looked for a stable version of the complex by screening the telomerase genes from dozens of different species. They found that the gene from the red rust flour beetle Tribolium castaneum was much shorter that of other species. This made the gene construct easier to handle when it was cloned into bacteria and allowed sufficient quantities to be grown and purified for use in the crystallography experiments. Their results are published in Nature2.

Skordalakes's study focused on the TERT protein subunit of the molecule, which is organised into a ring-like structure similar in shape to part of the reverse transcriptase enzymes found in the HIV virus. These similarities are not coincidental, says Skordalakes. They suggest a common evolutionary origin, and should encourage research into adapting anti-HIV drugs to block telomerase activity in cancer cells.

"The antiviral drug AZT has actually been used against cancer with limited success," says Skordalakes. "But now we know the three-dimensional structure of the active site we can zoom in on it and figure out why those inhibitors don't work so well. We can modify them to fit into that binding pocket more effectively and increase the potency of the drug."

Designer drugs

Telomerase remains active in some rapidly dividing adult cells, such as those in hair follicles and the testes. But the difference between its distribution in cancer cells and normal cells is much more marked than for the kinase enzymes which are the target of many anticancer drugs. That promises a realistic prospect of eventually producing highly specific drugs that are not cytotoxic for normal cells, says Skordalakes.

"This is a crucial part of the puzzle in understanding how telomerase works. Fundamental research like this may help scientists to design drugs that block telomerase and could potentially be used to treat a wide range of cancers," says Liz Baker, senior science information officer at the research charity Cancer Research UK.

Blackburn, now at the University of California, San Francisco, says that the work is "an important step along the way to the ultimate understanding of this enzyme, and for its potential exploitation for medical purposes".

However, she points out that the TERT subunit structure is not the end of the story. TERT collaborates with the RNA in telomerase to make DNA — a process that is still poorly understood. "So an important challenge still lies ahead: to figure out how that telomerase RNA-protein collaboration actually works," says Blackburn. 

  • References

    1. Greider, C. W. & Blackburn, E. H. Cell 43, 405–413 (1985).
    2. Gillis, A. J., Schuller, A. P. & Skordalakes, E. Nature advance online publication, doi:10.1038/nature07283 (2008).
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