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03/09/2006 08:00:00

Caltech Scientists Gain Fundamental Insight into How Cells Protect Genetic Blueprints

PASADENA, Calif.—Molecular biologists have known for some time that there is a so-called checkpoint control mechanism that keeps our cells from dividing until they have copied all the DNA in their genetic code. Similar mechanisms prevent cells from dividing with damaged DNA, which forms, for example, in one's skin after a sunburn. Without such genetic fidelity mechanisms, cells would divide with missing or defective genes.

Now, a California Institute of Technology team has uncovered new details of how these checkpoints work at the molecular level.

Reporting in the March 10 issue of the journal Cell, Caltech senior research associate Akiko Kumagai and her colleagues show that a protein with the unusual name "TopBP1" is responsible for activating the cascade of reactions that prohibit cells from dividing with corrupted genetic blueprints. The researchers say that their result is a key molecular insight, and could possibly lead to molecular breakthroughs in cancer therapy someday.

"The function of the checkpoint control mechanisms is to preserve the integrity of the genome," says William Dunphy, the corresponding author of the paper and a professor of biology at Caltech. "When these genetic fidelity mechanisms do not function properly, it can lead to cancer and ultimately death."

The research began with a study of a protein called ATR that was known to be a key regulator of checkpoint responses. This protein is a vital component of every eukaryotic cell (in other words, the cells of most organisms on Earth excluding bacteria). ATR is a "kinase," an enzyme that controls other proteins by modifying them with phosphate groups.

However, no one knew how the cell turns on this enzymatic activity of ATR when needed. To figure out how ATR gets activated in protecting against mutations has been one of the most urgent questions of the field for the past decade.

Acting on a hunch, the researchers decided to look at the TopBP1 protein, whose molecular function was hitherto mysterious. Strikingly, the team found that purified TopBP1 could bind directly to ATR and activate it. The activation was so quick and robust that the researchers knew immediately that they had found the long-sought activator of ATR and deciphered how cells mobilize their efforts to prevent mutations. Interestingly, the researchers found that only a small part of TopBP1 is necessary for activating ATR.

The researchers suspect that the remaining parts of TopBP1 hold additional secrets about checkpoint control mechanisms. Dunphy says that this molecular insight shows how a cancer-repressive mechanism works in a healthy cell. "Knowing how the normal system works might also help lead to insight on how to fix the system when it gets broken," he adds.

In addition to Kumagai and Dunphy, the other authors of the Cell paper are Joon Lee and Hae Yong Yoo, both senior research fellows at Caltech.

Written by Robert Tindol