Key cancer enzyme gives up its secret

Telomere (Image: Wikimedia Commons)

At the heart of almost all human cancers is a rogue enzyme, telomerase. Now the structure of a key catalytic component of the enzyme has been discovered, paving the way to more effective anti-cancer and, perhaps, anti-ageing drugs.

Telomerase is responsible for adding unique repetitive sequences of DNA, called telomeres, at one end of chromosomes. These telomere caps ensure the chromosomes don't fall apart, but because telomerase is dormant in most adult cells each time a cell divides, its telomere loses a chunk of DNA. Eventually, when cells can no longer divide, they die – this protects against cancer.

When telomerase is more active than it should be, telomeres don't get shorter. Instead, cells continue dividing beyond their normal limits, and become cancerous.

This has made telomerase a prime target for anti-cancer and anti-ageing therapies, but a lack of information on the structure of its catalytic subunit, TERT, has hindered progress.

Beetle bonanza

Emmanuel Skordalakes and his team from The Wistar Institute, Philadelphia, finally cracked the structure when they discovered that a gene in an insect – the flour beetle – could be harnessed to produce the enzyme in massive quantities.

This enabled the team to analyse TERT using X-ray crystallography.

"Structural studies of telomerase have been extremely difficult due to the size and complexity of the enzyme, which in turn made it difficult to isolate the protein component of telomerase in sufficient, stable quantities for the proposed studies," says Skordalakes.

The structural analysis reveals that TERT (telomerase reverse transcriptase protein) consists of three domains, and forms a ring-like doughnut structure that creates a central hole. When the telomere is being built, this hole allows a nucleic acid template molecule about eight nucleotide bases long to fit inside.

Anti-ageing drug?

Previously scientists had thought that the structure of the enzyme is similar to HIV transcriptase and developed anti-telomerase drugs accordingly. The structural analysis confirms there is a similarity, but it also reveals that one of the domains in the TERT protein – called the carboxy-terminal extension or CTE – has a unique type of protein fold, never been seen before.

This feature could help develop anti-telomerase drugs that specifically target the fold.

"Now that they know what the structure of the catalytic subunit is, they can design drugs that can bind to the protein subunit and either inhibit its activity for anti-cancer treatment, or promote its activity as anti-ageing therapy," says Stephen Neidle, from The School of Pharmacy, University of London, UK.

Neidle says developing drugs to target the enzyme could be used in combination with existing anti-telomerase anti-cancer therapies currently in clinical trials, such as a class of telomerase vaccines.

Aubrey de Grey of the Methuselah Foundation says: "If we had a really cast-iron therapy against all cancers, it might well be a good idea to stimulate telomerase, with a drug, for example, that might have widespread anti-ageing effects."

Journal reference: Nature (DOI:10/1038/nature07283)

Cancer - Learn more about one of the world’s biggest killers in our comprehensive special report.

Original here