Closing the loop on the end of a chromosome.

Photographs that reveal unsuspected genetic lariats at the ends of chromosomes have added a scientific spin to an old cliche. A picture can be worth a thousand experiments.

One of the hottest topics in biology, telomeres are stretches of repetitive DNA at the ends of chromosomes (SN: 11/25/95, p. 362). Telomeres prevent chromosome ends from sticking to each other and may play crucial roles in aging and cancer. They also somehow help cells avoid treating a normal chromosome tip as evidence of a broken chromosome. Such breaks normally prompt a cell to launch DNA-repair efforts or commit suicide.

Scientists had thought that telomeres consist of a linear DNA molecule, with one of the DNA's usually paired strands slightly longer than the other. This telomeric overhang posed a dilemma. Cells don't tolerate single-stranded DNA.

Some microscopic creatures called ciliates have proteins that bind to their telomeric overhangs and mask them. Yet attempts to find similar proteins in mammals, which have much longer overhangs, have so far proved fruitless.

During such searches, Titia de Lange of the Rockefeller University in New York and her colleagues did identify two proteins, TRF1 and TRF2, that bind to the double-stranded portion of mammalian telomeres. The scientists then joined forces with Jack D. Griffith of the University of North Carolina at Chapel Hill, who heads a research group that studies DNA-protein interactions.

The investigators synthesized telomeric DNA and mixed it with TRF1 or TRF2. Viewed under an electron microscope, telomeres exposed to TRF2 often displayed large circles, which the researchers named t loops, but no single-stranded ends. The overhang somehow had integrated itself into the double-stranded part of the telomere, they concluded. Telomeres isolated from mouse and human cells had the same loops, the scientists report in the May 14 CELL.

Cells lacking TRF2 activate DNA-repair machinery and sometimes even commit suicide, suggesting that telomeres require TRF2 to form loops, says de Lange. Such cells, as expected, seem to interpret unlooped telomeres as damaged DNA.

Why haven't biologists observed t loops before? Telomeres are only a small portion of a chromosome's DNA. "Unless someone had been looking for [a loop], it would be easy to miss," says Griffith. Future studies will explore how t loops form and what tricks other organisms employ to mask telomeric overhangs. "It may be that each creature has come up with its own solution," speculates Griffith.

Some researchers suspect that the wear and tear of aging results, in part, from telomeres dwindling. "Perhaps as a part of aging, a few telomeres get so short that they can no longer form t loops," says Jerry W. Shay of the University of Texas Southwestern Medical Center at Dallas.

Since t loops seem to hide the tips of telomeres, scientists now wonder how the enzyme called telomerase acts on telomeres' ends to maintain or extend their length. "The discovery of t loops solves some long-standing problems, makes others moot, and raises some new ones," notes Carol W. Greider of Johns Hopkins Medical Institutions in Baltimore in a commentary in CELL.

This telomere forms a large loop (left of arrow) that crisscrosses itself.