Jumpstarting DNA repair. (Genetic Research).
A team from the University of North Carolina at Chapel Hill have found that a protein named ATR directly binds to DNA. Their study, published in the 14 May 2002 issue of Proceedings of the National Academy of Sciences, adds to scientists' broad knowledge about cancer and how cells protect themselves from DNA damage. "The DNA damage checkpoint system is really what determines cell death or survival, in both normal cells and cancerous cells," says principal investigator Aziz Sancar, a professor of biophysics and biochemistry. "ATR is a key protein in understanding this system."
Scientists already knew that ATR was somehow involved in the damage checkpoint system, but some had speculated that an intermediary protein actually sensed the damage. "We demonstrated that, without an intermediary, ATR binds to DNA, and when there is DNA damage [ATR] binds with higher affinity," says Sancar. "It is the first biochemistry paper showing that this protein has affinity for damaged DNA and can sense the damage directly."
The researchers purified ATR from human connective tissue cells, then mixed the purified ATR with both damaged and undamaged DNA. They then measured the binding using different methods of biochemical analysis as well as electron microscopy. In one method, the researchers bound the ATR to carbohydrate beads, added radiolabeled DNA, washed the beads three times to eliminate unbound DNA, and then visualized the ATR-bound DNA by autoradiograph. Measuring the radioactivity indicated the amount of DNA bound to the ATR. The findings all showed that ATR bound directly to DNA, and bound with twice the affinity to damaged DNA.
The authors call the twofold difference in binding modest, but Jim Drummond, an assistant professor of biology at Indiana University Bloomington who specializes in the mechanisms of DNA repair pathways, says that small differences found during in vitro experiments can be significant in vivo. "When you look in the cell, those sort of small [DNA-level] differences can be amplified into very large [organism-level] differences," he says.
According to Drummond, the next logical step is to identify the specific sequence of cellular signals that make up the checkpoint system--how ATR's binding to damaged DNA results in a change in the cell cycle and the actual repair of the DNA. Understanding that sequence could eventually provide researchers with dues to possible gene targets for drugs or other therapies.
|Printer friendly Cite/link Email Feedback|
|Publication:||Environmental Health Perspectives|
|Date:||Dec 1, 2002|
|Previous Article:||Profiles in cancer. (Molecular Biology).|
|Next Article:||EHP Toxicogenomics. (ehpnet).|