May 17, 1999 CHAPEL HILL - Scientists at the University of North Carolina at Chapel Hill's Lineberger Comprehensive Cancer Center and Rockefeller University appear to have solved an important and long-standing mystery in cell biology. The puzzle is why cells' internal repair machinery doesn't mistake the ends of chromosomes for broken DNA and either "fix" or destroy them.
Working together, the researchers have discovered that mammals' chromosomes end in loops. Under intense magnification, those chromosome ends, or telomeres, look something like lassos.
A report on the findings appears as the cover story in the May 14 issue of the journal Cell. Lead authors are Drs. Jack Griffith, professor of microbiology and immunology at the UNC-CH School of Medicine, and Titia de Lange, professor and head of Rockefeller's Laboratory of Cell Biology and Genetics.
"We think this work is highly important because it should provide a whole new way of thinking about basic molecular mechanisms related to cancer and to control of aging in cells," Griffith said.
Genetic information in cells is stored in 46 long thread-like molecules called DNA, and each is packaged into a rod-shaped structure called a chromosome, he explained. When cells are exposed to X rays or other insults that break DNA molecules, the repair mechanisms stitch the broken ends back together. If too many breaks occur, then a cellular suicide response kicks in, and cells die.
"The question has been why natural chromosome ends, of which there are 92 per cell, do not trigger that response," the scientist said. "We believe we've found the answer."
For the first time, the researchers have produced photographs that show the loops clearly.
"The first clue came from studies by Dr. de Lange's group of one of the proteins they had discovered," said Griffith, whose laboratory employs electron microscopes to investigate the architecture of DNA molecules. "When this particular protein was functionally removed from the cell, the cell suicide response was triggered, which implicated the protein in masking the chromosome ends."
That finding encouraged the Rockefeller and UNC-CH teams to carry out experiments to examine how the protein might arrange DNA molecules containing genetic sequences typical of telomeres, he said. Resulting electron microscope images showed DNA molecules arranged into the lasso-like structures.
"DNA typical of the chromosome end, or telomere, was looped back around and attached to a distant internal site on the DNA and held there by the added protein," Griffith said. "The loop thus formed disguised the DNA end, keeping it cloaked or hidden from the sensors that trigger the cell suicide response."
Researchers then clipped DNA away from the ends of both human and mouse chromosomes, revealing very large loops, he said. While those structures appeared huge in photographs, they measured only 1/3000th of an inch around and comprised only 1/1000th of the chromosomes' total DNA.
Because chromosomes shorten as people age, many scientist believe telomeres play some unexplained central role in the body's lifelong biologic clock, Griffith said. Thus, telomeres may be some kind of regulator of cell death.
"Very rarely these days in science does a new result emerge from ongoing research, loop around, bite you from behind and make you say - Hey!" wrote Dr. Carol Greider of Johns Hopkins University in an accompanying editorial in Cell. "But this is just what has happened in the telomere field... .These results will make us re-think the classical view of telomere function that has emerged over the past 20 years and give a context in which a new synthesis will emerge."
The National Institutes of Health supported the research at both laboratories.
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