Protein Puts the Brakes on Fragile Site Breaks

Thomas Glover and Anne Casper Photo: Gregory Fox

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 these breaks don’t always occur at random. Instead, chromosomes break at just a few specific locations during stages in the cell cycle when DNA is being copied, or replicated, and the cell is dividing into two identical daughter cells.

Arrows point to fragile site gaps or breaks in chromosomes. Photo: Anne Casper

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 in a previously unknown molecular pathway protects fragile sites from breaking during DNA replication. Results of their research were published in the December 13, 2002, issue of Cell.

“ATR recognizes areas called stalled replication forks where the DNA-copying process is blocked,” says Anne M. Casper, a U-M graduate student in human genetics who is first author of the Cell paper. “For reasons we don’t understand, fragile sites seem to be difficult to copy. When replication starts to stall, ATR sends out a chemical signal telling the cell to shut down replication until it can fix the problem.”

Artist’s depiction of a stalled replication fork in DNA. Illustration: ClearScience

“If you complete the cell cycle without replicating the fragile site and the cell continues into metaphase, our hypothesis is that the cell goes into metaphase with a gap in the chromosome,” says Glover. “That can lead to double-strand breaks, chromatid recombination and all sorts of things that aren’t supposed to occur.” Since fragile site breaks are very common in some tumor cells and often take place near genes associated with tumors, defects in the ATR protein pathway may be involved in the progression of cancer.

The research study was funded by the National Institutes of Health. Casper is supported by a predoctoral fellowship from the National Science Founda-tion. Martin F. Arlt, Ph.D., a U-M post-doctoral fellow in human genetics, and Paul Nghiem, Ph.D., a Howard Hughes Medical Institute post-doctoral fellow at Harvard University, were collaborators on the study.

—SFP

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