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Chromosomes are ’nibbled’ before they fuse, researchers report


Discovery may have implications for stabilizing chromosomes in cancer cells

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 "breakage-fusion-bridge" pathway, a cell interprets chromosomes with short telomeres as being broken, and sets in motion machinery to "fix" the break by fusing it to another exposed end. The unintended consequence of this fix is the connection of two chromosomes. If the fused chromosomes are pulled to opposite sides of a dividing cell, they form a bridge that breaks randomly as the cell divides, and the process begins again.

To test whether this was the correct or only scenario, Hackett inserted genetic markers into a yeast chromosome to reveal where genetic damage most often occurs when telomeres got too short. Instead of random damage, she discovered that the marker at the very end of the chromosome was most likely to be lost, and the marker closest to the chromosome’s center the least likely.

"If fusion and breakage was the primary mechanism of gene loss, the pattern of loss would have been random -- each marker would have been just as likely as the others to be lost," explains Greider. "The marker loss we saw was not at all random, so we knew some other mechanism was at work."

Then, Hackett studied the engineered chromosomes in yeast missing an enzyme called exonuclease that normally recognizes and chews up broken chromosomes one strand of DNA at a time. Without the enzyme there were fewer chromosome rearrangements, offering strong evidence that this enzyme is doing the damage.

"Fusion happens, but it’s not the primary mechanism that triggers gene loss after telomeres get too short," says Greider. "Instead, exonuclease activity causes the bulk of immediate gene loss."

To prove that fusion does indeed result in a random pattern of marker loss, Hackett made an artificial fused, or di-centric, chromosome, complete with genetic markers to identify which segments were destroyed. Since Hackett engineered it, this fused chromosome could not already have been "nibbled" by an exonuclease.

"We demonstrated that fused chromosomes do break randomly, at which point exonucleases attack the exposed ends," says Greider. "Fusion is a big part of what leads to major genomic instability when telomeres aren’t working, but it’s not the initial problem. Our discovery should spark researchers in the field to think along new lines."

Greider cautions that they still need to verify that the same mechanism is to blame for genomic instability in mammalian cells as in yeast. If so, identifying other proteins that work with exonucleases may offer a target to block the process and push cells in cancer toward death instead of genomic instability.

Hackett is now a postdoctoral fellow at Harvard Medical School. Hackett was funded by the Johns Hopkins Predoctoral Training Program in Human Genetics and Molecular Biology and the National Science Foundation. The studies were funded by the National Institute of General Medical Sciences, part of the National Institutes of Health.

Joanna Downer | EurekAlert!
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