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Chromosomes are 'nibbled' before they fuse, researchers report

Overturning 60 years of scientific presumption, new evidence from Johns Hopkins scientists shows that enzymes nibble away at chromosomes when the chromosomes' protective tips, called telomeres, get too short.

Much like the plastic tips on shoelaces, telomeres protect the ends of chromosomes. When telomeres get too short, cells usually die. If they don't, the unprotected ends drag the chromosomes through an ugly assortment of fusions that lead to rearrangements, deletions and insertions that scramble the cell's genetic material and can lead to cancer. Until now, scientists had presumed that the fusions were the first thing to happen when telomeres stop protecting the chromosomes.

"We have always thought that if we can understand how shortened telomeres create genomic instability, we might be able to find targets in that process to push abnormal cells toward death and away from trying to repair themselves," says Carol Greider, Ph.D., professor and director of molecular biology and genetics at the Johns Hopkins School of Medicine. "Now it turns out that what we've always thought was the first step in the process is not the first step at all."

Writing in the December issue of Molecular and Cellular Biology, Greider and Hopkins graduate student Jennifer Hackett describe experiments with yeast which revealed that instead of just sticking, or fusing, end-to-end, chromosomes whose telomeres are too short are first nibbled by enzymes that normally clean up broken chromosomes.

"The fusion pathway was our favorite model of what goes wrong first when telomeres get too short. All the papers use that model to describe how loss of telomere function causes genomic instability," says Greider. "But just because we see a lot of something, doesn't mean it's the first thing that happens. We were quite surprised to find that fusion isn't the first effect of short telomeres."

In the traditional fusion scenario, officially called the "b
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
2-Dec-2003


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