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Biologists at Tufts University discover 1 reason why chromosomes break, often leading to cancer

o look at the region in a more detailed way than looking at human chromosomes and to monitor the replication process. They expect the results will be similar when tested in human cells based on previous research using yeast chromosomes.

"What we did was take two of these regions of predicted high flexibility, plus a region near a cancer cell breakpoint and a control region, and test whether any of these regions could cause breakage of a yeast chromosome," Freudenreich said. "We found that one did. This is exciting because it is the first known sequence element within a human common fragile site shown to increase chromosome breakage. What is intriguing is that the sequence that breaks, in addition to being flexible, is predicted to form an abnormal DNA structure."

When replication stalls, chromosomes can break

Next, the researchers had to determine how the chromosomes were breaking. From past studies, they hypothesized that breakage was connected to "replication." As cells divide, the DNA inside those cells must duplicate, which is called replication. The Tufts research showed that the chromosomes were breaking because replication was stalled.

"We found that the fragile sequence actually stops replication," Freudenreich said. "So when replication gets there, it has trouble, it stops, it pauses, it can't go further very easily."

Most of the time, chromosomes break and heal correctly. The problem arises when they do not heal correctly and instead are deleted or rearranged, Freudenreich explained. "Cancer cells almost always have some sort of deletions or rearrangements," she said. "Something is wrong with their chromosomes that then messes up the genes that are in those areas."

The researchers also noticed that this particular sequence was an AT-rich region, where the DNA was composed mostly of the bases adenine (A) and thymine (T), rather than the other bases cytosine (C) or guanine (G). Freudenreich
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Contact: Suzanne Miller
suzanne_c.miller@tufts.edu
617-627-4703
Tufts University
2-Aug-2007


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