January 8, 1997

Media Contacts: Sarah Goodwin, 404/727-3366 - sgoodwi@emory.edu
Kathi Ovnic, 404/727-9371 - covni c@emory.edu

Suppose you were repairing the hole in your roof, but before you could finish the job other holes began to appear. If this continued, you might not complete all the repairs before the whole roof caved in! Human cells are constantly faced with the need to repair damage to their DNA from UV light, chemicals, man-made sources like gamma radiation, and oxygen byproducts. They are quite adept at these repairs as lo ng as they are given the time.

About eight years ago scientists discovered that the cell cycle includes safety mechanisms they named checkpoint arrests, in which cells are given the chance to stop dividing long enough to complete appropriate r epairs accurately before continuing with mitosis or DNA replication.

Emory's Winship Cancer Center investigator Wolfram Siede, Ph.D., recently received an NIH R01 grant to study cell cycle regulation and checkpoint control using a yeast model a nd cells damaged by UV radiation and chemicals.

"If damage to a cell's genome is not repaired or is incorrectly repaired," says Dr. Siede, "genetic instability may result, which may be the first step to accumulating genetic changes that event ually lead to cancer. The human P53 gene, for example, which is altered in 50 percent of cancer cells, is one of the regulators of checkpoint arrest. Checkpoint arrest is especially important for dividing cells, because they are continuously progressing in the cell cycle. A checkpoint is like a border station, where cells stop long enough to check the damage, repair it, then go on."

In working with the yeast model, which already has a completely sequenced genome, Dr. Siede is studying severa l genes known to be regulators of checkpoint processes. By analyzing mutants of these genes and their resultant proteins, he hopes to find out what makes cells stop at checkpoints, what constitutes the signal to stop, and how the signal is transmitted fr om the damaged DNA to the cell-cycle regulating molecules.

"Understanding why a cancer cell fails to use repair checkpoints goes to the molecular origins of cancer," Dr. Siede points out. "The more you know about these defective checkpoints, th e easier it will be to exploit this knowledge to test and develop therapeutic agents."

By using the mutant yeast genes, he will be modeling cancer cells, which have mutations that cause them not to use checkpoints to react to the challenges pre sented by DNA damage. At least one of these genes has a human homologue, the gene responsible for ataxia telangiectasia (AT), an inherited syndrome that causes early death, a proclivity to cancer, and a sensitivity to radiation treatment.


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