Biologists solve a genetic mystery

Human chromosomes are tied in large knotted loops

October 08, 1999|By Nicholas Wade | Nicholas Wade,New York Times News Service

Biologists must have gazed thousands of times through microscopes at the 46 chromosomes that lie in the nucleus of every normal human cell without perceiving what has now been discovered: the ends of the chromosomes - the immensely long molecules of DNA that carry the genetic information - are neatly tied in large, firmly knotted loops.

The discovery bears on a long- puzzle, that of why the cell does not mistake the ends of intact chromosomes for the broken ends of cut chromosomes. A broken chromosome end sends the cell into full panic mode: If it cannot repair the broken end it will trigger its self-destruct mechanism and die for the common good rather than risk the genetic instability that leads to cancer.

The loops provide the answer that no one had divined: Normal chromosomes have no ends, only the perfect topological continuum of a circle.

'New way to think'

"This gives us a whole new way to think about how the telomeres may function," said Dr. Carol W. Greider of Johns Hopkins University, referring to the end sections of the chromosomes.

The discovery could lead to important insights about cancer and longevity, with which the telomeres are intimately connected. Each time a cell divides, its telomeres get shorter, as if marking off a finite number of permissible divisions. When the telomeres get too stubby, the cell is thrown into senescence and dies.

Biologists recently got a taste of immortality when they found that human cells kept in culture would grow and divide indefinitely if their telomeres were artificially lengthened. But the idea of extending the technique into the body has been criticized on the ground that telomere shortening is a last defense against the runaway cell divisions of cancer.

The discovery seems immediately to explain the mechanism behind these important findings: When the telomeres get too short, presumably the cell can no longer bend them to form loops. A naked chromosome end then appears, tripping the cell's hara-kiri program.

'An exciting finding'

"It's an exciting finding because biomolecular structure and function always go hand in hand," said Dr. Thomas Cech, a telomere expert at the University of Colorado.

The new finding, published in a recent issue of Cell, is the work of Titia de Lange of the Rockefeller University in New York and Jack Griffith of the University of North Carolina at Chapel Hill.

De Lange had been trying for years to find out how the ends of the chromosomes were capped, suspecting that they might be swathed in some special protein that concealed them from the cell's self-destruct mechanism.

Several years ago she found a protein that would glue itself along the telomeres. But strangely, it did not stick to the very end.

A year ago she turned to Griffith, an expert at studying DNA-protein interactions under the electron microscope. At first they saw very odd structures that were hard to explain. Further experiments gave a clearer picture. "When I saw these loops, I didn't really believe it," De Lange said. "We were quite concerned it might be an artifact."

One reason the loops had never been noticed before is the enormous length of DNA. Each cell has about 6 feet of DNA. Although there must be 92 terminal loops in each full set of 46 chromosomes, they would be hard to notice among the many accidental circles made by DNA molecules when they are spread out on a microscope slide. "If you take spaghetti and sling it on the floor, you'll occasionally see a little lassolike thing," Griffith said.

As in the rest of the double-stranded DNA molecule, the telomere regions are cross-linked until the very end, where one strand extends alone for about 200 bases, as the chemical units of DNA are known. This overhang of unpaired bases has turned out to be the clasp that seals the loop.

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