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ShareSep. 30, 2011 — Our cells' life span is determined by telomeres, genetic elements located at chromosome extremities. Telomeres erode after each cell division, which leads to cellular aging. Normally, the reaching of a critical shortening provokes an active process of programmed cell death. Tumor cells, however, evade this control system, whose functioning must thus be deciphered. Researchers in Switzerland have discovered a protein capable of regulating the length of telomeres and protecting them.
Most of our cells are programmed to divide a definite number of times before declining. This process is regulated by the telomeres, repetitive DNA sequences that constitute chromosome extremities. Telomeres shorten until they reach a critical size, at which point the cell becomes senescent. Each cell has thus its own 'quality control' label, with the length of the telomeres providing a use-by date.
When the hourglass gets blocked
Various types of cells, however, are not submitted to this control. This concerns namely reproductive and stem cells, because they need to proliferate without being hampered, as well as cancer cells. This relative immortality is mainly due to the activity of telomerase, an enzyme capable of elongating the extremities of DNA strands. It is thus mandatory to understand telomerase and telomere length regulation, which are promising targets for anti-cancer therapeutics. Telomeres have to be continuously maintained so that the cell hourglass may function with precision. Protected by a 'cap' of proteins, telomeres undergo controlled erosion resulting from the competition between enzymes that elongate them and those that degrade them.
David Shore, member of the NCCR Frontiers in Genetics, investigates the mechanisms involved in yeast, a model for mammal cells.
How to distinguish DNA's natural extremities
The professor's team studied the role of a protein called Tbf1, which binds to sites immediately upstream of telomeres: "We discovered that Tbf1 is able to regulate the length of telomeres and to prevent them from being recognized as a DNA break." This protein thus allows the cell to distinguish between chromosome ends and accidental DNA breaks, the latter of which must be repaired to maintain chromosome stability. Human cells have a protein closely related to Tbf1, which interacts with their telomeres in a similar way. This molecule certainly also plays a protective role of these extremities, since an alteration of its function has been revealed in some forms of cancers.
The telomerase is present, albeit muzzled
A surprise awaited the authors of this study, performed at the University of Geneva, Switzerland. The telomerase was hitherto known to interact only with telomeres, in order to elongate them. "We discovered that this enzyme binds in fact to all damaged DNA strands, at the site of the break. However, the telomerase is inactive, thus preventing them from being inadvertently converted into telomeres," explains Virginie Ribaud, member of the team at the department of Molecular Biology. The researchers' next step will be to uncover which mechanisms are involved in the enzyme's inhibition, in case of danger, as demonstrated here.
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The above story is reprinted from materials provided by Université de Genève, via AlphaGalileo.
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Journal Reference:
- Virginie Ribaud, Cyril Ribeyre, Pascal Damay, David Shore. DNA-end capping by the budding yeast transcription factor and subtelomeric binding protein Tbf1. The EMBO Journal, 2011; DOI: 10.1038/emboj.2011.349
Note: If no author is given, the source is cited instead.
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