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Checkpoint protein blocks chromosome breaks at fragile sites

ANN ARBOR, MI With 46 chromosomes and six feet of DNA to copy every time most human cells divide, it's not surprising that gaps or breaks sometimes show up in the finished product especially when the cell is under stress or dividing rapidly, as in cancer.

But what is surprising according to Thomas Glover, Ph.D., a geneticist at the University of Michigan Medical School is that the breaks don't always occur at random. They happen at a few specific locations on chromosomes, when cells are under stress, during the stages in the cell cycle where DNA is copied, or replicated, and the cell splits into two identical daughter cells.

Scientists call them fragile sites, but the reasons for their inherent instability have remained a mystery. Now Glover and colleagues at the U-M Medical School and the Howard Hughes Medical Institute have discovered that a protein called ATR protects fragile sites from breaking during DNA replication. Results of their research will be published in the Dec.13 issue of Cell.

The discovery is significant because it is the first evidence of a major molecular pathway that regulates genome stability at chromosomal fragile sites. Since fragile site breaks are very common in some tumor cells and often occur near genes associated with tumors, defects in the ATR protein pathway may be involved in the progression of cancer.

Seventy-five fragile sites have been identified in the human genome, but most are rarely seen, according to Glover, a U-M professor of human genetics and of pediatrics, who directed the study. "Twenty sites account for 80 percent of all chromosome breaks, and five sites are responsible for nearly half the breaks," says Glover.

Fragile sites are large and can extend over hundreds of thousands of DNA base pairs. "The most common fragile site, FRA3B, spans at least 500 kilobases," says Anne M. Casper, a U-M graduate student in human genetics and first author on the Cell paper. "In different me
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Contact: Sally Pobojewski
pobo@umich.edu
734-615-6912
University of Michigan Health System
12-Dec-2002


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