Scientists discover protein identifies damage to DNA

May 13, 2002

(Embargoed) CHAPEL HILL - Scientists at the University of North Carolina at Chapel Hill have identified a protein that becomes part of the critical process by which the genetic information called DNA repairs itself following damage by sunlight, pollution or other trauma.

The protein, which is called ATR and already was known, senses damage to DNA so that the body's natural repair system can kick into action, the researchers found.

A report on the UNC School of Medicine findings appears in the May 14 issue of the Proceedings of the National Academy of Sciences. Authors are postdoctoral associates Keziban Unsal-Kacmaz and Alexander M. Makhov and Drs. Jack D. Griffith and Aziz Sancar, Kenan professor of microbiology and immunology and Kenan professor of biophysics and biochemistry, respectively.

Ultraviolet radiation, pollution and chemotherapy cause mistakes in DNA that must be repaired before the cell divides and propagates the mutations as cancer or other problems, Sancar said.

Redundant proofreading and repair systems exist that pinpoint the affected genetic sequences, cut them away and build them back right.

"Little is known, however, about how this molecular fix-it team recognizes the problem," Sancar said. "In this new work, we report that we have identified one piece of the molecular alarm system that starts the cascade of DNA repair and cell cycle checkpoint."

The downstream effects of the ATR alarm protein were already known, but it was unclear if ATR sensed damaged DNA directly or if it was just part of the cascade, activated by another sensing protein upstream from it, he said.

"To find out if ATR directly sensed damaged DNA, we put a molecular tag on the ATR protein and purified it," Sancar said. "We incubated the tagged protein with either bits of DNA that were normal or damaged by UV radiation. ATR bound more often to damaged DNA than to undamaged DNA.

"Also, upon interaction with damaged DNA, ATR's activity increased," he said. "These results suggest that ATR senses damaged DNA and helps to start the cascade of DNA lesion repair."

Scientists call the natural mechanism the DNA damage checkpoint system. The researcher who discovered it originally, Dr. Leland Hartwell, received the Nobel Prize last year for his work.

"This is a very important phenomenon in both normal and cancerous cells, and there has been a great deal of research about it," Sancar said. "ATR appears to act as a switch that starts the repair process and also stops cells from proliferating while they are being repaired. This new work is not going to cure cancer by itself, but it is a significant step forward."

Now that the protein's role is known, other scientists can screen for drugs that act on it.

Griffith and Sancar are members of the UNC Lineberger Comprehensive Cancer Center. They and their postdoctoral fellows worked on human cells known as fibroblasts.
-end-
The National Institutes of Health supports the research.

Note: Sancar can be reached at (919) 962-0115.

By DAVID WILLIAMSON
UNC News Services

University of North Carolina at Chapel Hill

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