New clue to how telomeres work

One protein appears to play an integral role in protecting telomeres, and possibly preventing cancerous growth, according to a study published this week in Science. Chromosomes with fluorescently tagged telomeres in cells that lack Rap1and Ku. The arrows point to examples of telomere-sister chromatid exchanges.Image: Titia de Lange laboratoryThe protein in question is part of a complex called shelterin, which prevents a potentially dangerous type of DNA repair that can shorten telomeres and

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One protein appears to play an integral role in protecting telomeres, and possibly preventing cancerous growth, according to a study published this week in Science.
Chromosomes with fluorescently tagged
telomeres in cells that lack Rap1
and Ku. The arrows point to examples of
telomere-sister chromatid exchanges.

Image: Titia de Lange laboratory
The protein in question is part of a complex called shelterin, which prevents a potentially dangerous type of DNA repair that can shorten telomeres and therefore cause cells to age quickly. Alternatively, the repair process can help elongate telomeres in cancer cells, allowing them to proliferate. This protein "is required in the complex to repress one of the two DNA repair pathways that can act on DNA ends," said cell biologist and study author linkurl:Titia de Lange;http://www.rockefeller.edu/research/faculty/abstract.php?id=130 of The Rockefeller University. "It's important for cells to repress this [because it can be] dangerous for telomeres, lead[ing] to abrupt changes in telomere length [that] can kill the cells or reset telomere length." "What I liked the most about the paper is how elegant and complete it is," said chromosome biologist linkurl:Virginia Zakian;http://www.molbio.princeton.edu/index.php?option=content&task=view&id=28 of Princeton University, who was not involved in the research. "They've demonstrated that one of the very specific roles of telomeres is mediated in part by this protein." Telomeres protect the ends of chromosomes from deterioration during DNA replication, but can actually be thought of as a chromosome's "Achilles heel," said molecular biologist linkurl:David Shore;http://www.molbio.unige.ch/shore/index.php of University of Geneva, who did not participate in the research. Because they resemble the ends of DNA accidentally broken by chemicals or radiation, he explained, telomeres can be targeted by the same DNA repair pathways aimed at mending accidental breaks. Whether the repair machinery tries to "fix" the telomeres by joining them together, as in the case of nonhomologous end joining pathway, or by homologous recombination between sister chromatids (homology-directed repair), the cell's natural processes can "create havoc in the genome." But telomeres are protected from such inappropriate repair mechanisms by a six-protein complex, known as shelterin, which guards telomeres against both types of DNA repair pathways, as well as two types of signaling pathways that help identify breaks and initiate DNA repair. One by one, de Lange and her colleagues have begun to parse out the roles for each of the shelterin proteins. "One could think that if you take one of the components out, the whole thing would fall apart," but instead, her experiments revealed that "there was some division of labor in the complex," she said. The fifth shelterin protein de Lange's group explored, Rap1, appeared to play a specific role in suppressing the cell's homologous recombination, which can cause the exchange of sister telomeres. By labeling two sister telomeres in two different colors -- one red and one green -- the researchers could literally see that the telomeres were swapping places in mouse embryonic fibroblasts with knocked out (or knocked down) Rap1, suggesting that the protein was essential to protecting the telomeres against this particular DNA repair pathway. In healthy cells, "telomere length is highly regulated," de Lange said, giving the cell a predetermined lifespan. But because of the nature of the telomeric DNA -- strings of repeated nucleotides -- these so-called telomeric sister chromatid exchanges can be dangerous by making it easy for the DNA to slip. This can cause the chromatids to exchange DNA sections of unequal length, resulting in one daughter telomere that is much shorter and one that is much longer. "The daughter cell that gets the shorter end could be in trouble because [it has fewer] divisions' worth of telomere reserves," de Lange said. On the other hand, the daughter cell that gets the longer end will live longer. This is the first step in a process known as telomere elongation -- a pathway of telomere maintenance activated in some tumor types that allows cancerous tissue to keep dividing beyond the normal lifespan of a cell. "[We've identified] the first step on how the telomeres [in healthy cells] avoid this pathway," de Lange said. Another way tumor cells elongate their telomeres is by upregulating telomerase, which is present in about 85 percent of tumors, de Lange added. Interestingly, while Rap1 is clearly essential for suppressing telomeric sister chromatid exchanges as a part of the shelterin complex, this is a redundant suppression pathway, Zakian noted. The Rap1 knockout mice were, in contrast to other shelterin knockouts, "just fine," she said. The role for Rap1 could only be seen when the researchers looked in cell cultures where another protein known as Ku had also been knocked out. It could be argued, de Lange said, that "this is a very important pathway to repress so it's repressed in multiple ways," but redundancy is not uncommon in regulatory pathways, she noted. de Lange's lab has already tackled the last piece of the puzzle -- the sixth shelterin protein. The results "will be coming," she said. "Once we know which protein" -- either alone or in combination -- "is dedicated to which pathway, we can begin to try to understand the mechanism by which these proteins act," she said. "That's what we want to know."
**__Related stories:__***linkurl:Telomere researchers win Nobel;http://www.the-scientist.com/blog/display/56039/
[5th October 2009]*linkurl:Clone telomeres behave normally;http://www.the-scientist.com/article/display/22181/
[18th May 2004]*linkurl:Telomeres as the Key to Cancer;http://www.the-scientist.com/article/display/13076/
[27th May 2002]
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Meet the Author

  • Jef Akst

    Jef Akst was managing editor of The Scientist, where she started as an intern in 2009 after receiving a master’s degree from Indiana University in April 2009 studying the mating behavior of seahorses.
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