TAM London 2009 Day 1 minipost – Simon Singh wins award Can a conference change the world?
Oct 07
Posted by: colinhockings

Telomere Caps

Most denizens of the interwebs (at least of this corner of the interwebs) will have heard the announcement that the 2009 Nobel Prize in Physiology or Medicine will be given to Elizabeth Blackburn, Carol Greider and Jack Szostak for their work on telomeres – the structures found at the ends of human chromosomes. You may already have read a little about the research behind it (if not, the NobelPrize.org press release is a very good place to start) so I’ll try to keep the background as short as possible. What I would like to do here is to explain the assertions that “cancer research has also benefited from the Nobel-winning trio’s work”.

Telomeres are necessary for several reasons, among them to act as ‘padding’ during cell duplication. Every time a linear DNA molecule is replicated it loses a few base pairs from the ends (the reason why is quite interesting, see this description of the end replication problem). The telomeric sequence is simply “TTAGGG” (in vertebrates) repeated several thousand times so it doesn’t matter when some sequence is deleted. But, I hear you cry, how is this important for cancer?

Most cells in the body do not replicate. A typical tissue, such as skin, has a thin layer of stem cells that divide to produce more stem cells, as well as cells that will differentiate into skin cells. These cells divide a few more times until they are ‘terminally differentiated’. In the case of skin that means that they are filled with keratin and die, and when they reach the surface they are sloughed off. In other tissues the non-replicating terminally differentiated cells have different functions, for example as nerve cells or muscle cells. Thus the only cells that need to replicate infinitely are stem cells (and germ line cells, the cells that become sperm and eggs), so they express a protein called telomerase which adds extra copies of the repetitive sequences to the ends of chromosomes.

Those of you who’ve read my first ‘Understanding Cancer’ post – and anyone who knows a little bit about cancer biology – will see why this system is a major inhibitor of carcinogenesis: when a cell starts to over-proliferate it can only divide a certain number of times before the telomeres are fully eroded. In order to continue dividing it has to accumulate further mutations that render it immortal. These mutations have to be very specific, making them rarer: there are thousands of ways to make a cell grow faster, but only very few ways to lengthen its telomeres. Around 90% of cancers (remember: a cancer is, by definition, a collection of cells that have jumped this hurdle) have mutations that cause them to produce telomerase. Most of the remaining cases of cancer have recruited a normal DNA repair mechanism to lengthen the chromosomes by a process called ALT (Alternative Lengthening of Telomeres).

On a short side note: when telomeres were first elucidated it was thought by some that we’d found the key to aging. Unfortunately upregulating telomerase in an attempt to stay young only leads to more cancer, because you’ve removed one of the hurdles that a nascent tumour has to surmount.

Does anyone see the further significance here? All cancers have to overcome a certain problem, and most of them do it in exactly the same way. This makes telomerase a very attractive target for new chemotherapeutic drugs or other types of intervention, and the field is bustling with new ideas. A few clinical trials are showing progress, using gene therapy and small molecule inhibitors (a.k.a. drugs): for a fuller account read this nice open-access review. The approach that strikes me as the most fascinating – and promising – is the idea of vaccinating against telomerase. Almost all cells in the body constantly chew up a sample of their own proteins and display them to the cells of the immune system as a defence against viruses. If you can tell the immune system to attack cells that express telomerase (not quite as straightforward as one might think) it will specifically attack cancer cells. This should be more specific (read: cause less side effects) than most anti-cancer therapies because most drugs attack all rapidly-replicating cells, whereas this would only target immortal cells, and just like you may have learnt from comic books: immortality is a very rare privilege.

ResearchBlogging.orgShay, J., & Keith, W. (2008). Targeting telomerase for cancer therapeutics British Journal of Cancer, 98 (4), 677-683 DOI: 10.1038/sj.bjc.6604209

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8 Responses to “Understanding Cancer Part 2 – Telomerase, the Road to Immortality, and the Nobel Prize”

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  3. Leonel O. Ingram Says:

    complicate such therapies. Some have reported ALT methods of telomere maintenance and storage of DNA in cancer stem cells, however Geron claims to have killed cancer stem cells with their telomerase inhibitor GRN163L at Johns Hopkins. GRN163L binds directly to the RNA template of telomerase. Even a mutation of the RNA template of telomerase would render the telomerase unable to extend telomeres, and therefore not be able to grant replicative immortality to cancer, not allow glycolysis to be inititated, and not upregulate Blackburn’s 70 cancer genes.

  4. Arron Webster Says:

    These observations indicated that TERT possesses properties of a developmental regulator and indeed TERT exerts these potent developmental effects as a modulator in the Wnt signaling pathway ( 149 ). TERT interacts with the chromatin remodeling protein Brg-1, which binds β-catenin, the central transactivator in the Wnt pathway. TERT is recruited to Wnt target gene chromatin in cells stimulated by Wnts and serves to enhance the transcriptional output of the Wnt program in this context ( 148 , 149 ). The ability of TERT to enhance Wnt signaling explains how TERT activates bulge stem cells since overexpression of β-catenin in mouse skin causes a very similar stem cell-activation phenotype ( 150 – 152 ). In addition, TERT was shown to interact with RNA component of mitochondrial RNA processing endoribonuclease, the RNA component of ribonuclease P, and in this context TERT is able to act as an RNA-dependent RNA polymerase. These findings suggest that TERT may amplify small non-coding RNAs and exert other activities through this mechanism ( 153 ). Together, these findings indicate that the near universal reactivation of TERT in human cancers may promote tumor progression, proliferation or survival through multiple mechanisms. Upregulation of TERT may yield enhanced telomerase activity and therefore stabilize short telomeres, supporting unlimited cell division. In addition, by enhanceing Wnt signals in human tumors, TERT may support proliferation and survival of cancer cells through more direct mechanisms.

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