Short and Solid: Telomere binding protein strengthens, not lengthens (Telomeres; Cellular senescence)

Abstract

They say that size doesn't matter. And if the subject is telomeres--the caps that guard our chromosomes' ends--the adage might actually be true. New research bolsters the notion that when it comes to keeping cells youthful, it's not the absolute length of telomeres that's important, but whether these structures can still do their job: keeping raggedy old chromosomes from alerting cells that it's time to stop dividing or even to self-destruct. Telomeres--repetitive stretches of DNA adorned with proteins--shrink every time a cell duplicates. This observation led researchers to speculate that cells might use telomere size to gauge their age. Studies of cell cultures support the hypothesis: As human cells proliferate in a culture dish, their telomeres shorten until the cells senesce, entering a state in which they no longer produce offspring (see "More Than a Sum of Our Cells" ). What's more, restoring telomeres to their youthful proportions--by adding an enzyme that rebuilds them--endows cultured cells with immortality, allowing them to divide apparently forever. But what is it about older telomeres that signals a cell to renounce reproduction? Is it purely a matter of magnitude? Must these chromosomal caps disappear entirely before an aging cell senesces? Karlseder and colleagues say no. The researchers were studying TRF2, one of the proteins that decorates and protects telomeres. Previous work showed that when TRF2 is missing, cells treat their chromosome ends as broken DNA--a misjudgment that leads to chromosome fusion and eventually cell suicide (see "Dangerous Liaisons" ). To learn more about how TRF2 camouflages chromosome tips, the researchers overproduced this protective protein in cultured human fibroblasts, a type of connective tissue cell. Oddly, the telomeres in these cells eroded more rapidly than did those in control cells, vanishing at a rate of 165 to 180 base pairs per generation, as opposed to the 100 base pairs lost by normal cells. Perhaps TRF2 draws a DNA-trimming enzyme to the telomeres, the authors propose. The accelerated telomere depletion, however, did not translate into premature senescence. Cells with extra TRF2 remained vibrant even after their telomeres had dwindled to about half the length of telomeres that discourage division in untreated cells. From these results, the researchers drew two conclusions. Because telomeres persist in senescing cells, the structures don't evaporate entirely before cellular duplication ceases. Furthermore, telomere length per se does not dictate senescence. Instead, the authors posit, the structures decay as cells age, and at some point the stubbiest ones can no longer attract the TRF2 they need for protection. The length at which luring TRF2 becomes a problem is not yet known. The study is important because "it gets us away from the simple view that it's all about telomere attrition," says Ron DePinho, a cancer geneticist at Harvard Medical School in Boston, "and it fortifies the view that 'It's the function, stupid.' " --Karen Hopkin A related question: How many telomeres does it take to trigger senescence? Click "Comment on Article" to discuss this issue. J. Karlseder, A. Smogorzewska, T. de Lange, Senescence induced by altered telomere state, not telomere loss. Science 295 , 2446-2449 (2002). [Abstract] [Full Text]