Sci. Aging Knowl. Environ., 26 March 2003
Vol. 2003, Issue 12, p. nw49
[DOI: 10.1126/sageke.2003.12.nw49]

NOTEWORTHY ARTICLES

Senescence Tip-Off

Tacky telomere ends erode as cells age

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/12/nw49

Key Words: telomere-oligonucleotide ligation assay • p53 • Rb

As cells age, their chromosome ends erode, but whether short tips spur death remains unclear. New work uncovers a signal that might prompt cells to stop dividing. The study reveals that the sticky strands that compose the DNA extremes disappear as cells shudder to a halt, although further work is needed to clarify whether the loss causes death or simply occurs simultaneously.

Like the organisms they constitute, cells suffer the effects of age. In culture, they eventually stop dividing and enter an inactive state known as senescence (see "More Than a Sum of Our Cells"). Telomeres--repetitive DNA sequences and proteins that protect the ends of chromosomes--shrink each time a cell splits, and their disappearance seems to signal senescence. When they get too short, alarm systems tell cells to call it quits. But the telomere signal doesn't always ring as expected (see "Napoleonic Demons" and "Short and Solid"). Some cell types with long telomeres senesce, but others with short ones keep growing--so scientists have been hunting for other telomere characteristics that cripple cells. At telomere ends, one DNA strand extends beyond the other, leaving an unpaired overhang. This overhang helps seal telomeres into a stable, looped structure. In the new work, cancer researcher Robert Weinberg of the Massachusetts Institute of Technology in Cambridge and colleagues probed whether telomere overhangs erode with time and possibly trigger senescence.

The researchers used a new method to measure overhang length. They collected DNA from cells and added short, radioactive DNA molecules that match the repeated telomere sequence, which is present in the overhang. Then they added an enzyme that seals those short pieces and measured the size of the resulting--longer--segments. These radioactive molecules serve as rulers for overhang length: The more generous the extension, the more short pieces of DNA had bound and linked together.

The team used the technique to measure overhang lengths as two different cell types aged. In human foreskin cells and lung connective tissue cells, DNA extensions remained relatively stable as cells divided and then suddenly shrank in the last few cycles before senescence. Engineering cells to produce telomerase, an enzyme that adds DNA to the overhanging ends, delayed senescence. When the researchers disarmed proteins that halt cell division--which delays senescence but does not slow overall telomere shrinkage--overhangs withered. Together the results suggest that the disappearance of overhangs precedes and perhaps triggers senescence, rather than results from it.

The notion that shriveled overhangs spur senescence "is a thought-provoking idea," says dermatologist Barbara Gilchrest of the Boston University School of Medicine, but "the data don't lock down the hypothesis." She and her colleagues recently showed that supplementing cells with short pieces of DNA that bear overhang sequences provoked senescence. That result apparently contradicts the new work by suggesting that the presence, rather than the absence, of the overhang sequence halts cell division. But Weinberg counters that the extra pieces might be spiriting away proteins necessary to stabilize telomeres. Future work might clarify the sticky point of whether fading telomere tails provoke senescence.

--R. John Davenport; suggested by Greg Liszt


March 26, 2003
  1. S. A. Stewart et al., Erosion of the telomeric single-strand overhang at replicative senescence. Nat. Gen., 24 March 2003 [e-pub ahead of print]. [Abstract/Full Text]
  2. G. Z. Li, M. S. Eller, R. Firoozabadi, B. A. Gilchrest, Evidence that exposure of the telomere 3' overhang sequence induces senescence. Proc. Natl. Acad. Sci. U.S.A. 100, 527-531 (2003). [Abstract/Free Full Text]
Citation: R. J. Davenport, Senescence Tip-Off. Sci. SAGE KE 2003, nw49 (26 March 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/12/nw49








Science of Aging Knowledge Environment. ISSN 1539-6150