Common genetic damages in non-dividing cells lead to the creation of mutan...( on. A second type of genetic damag...)

A second type of genetic damage is caused by 8-oxoguanine, another base substitution that frequently results from the formation of oxygen radicals during normal cellular metabolism.

"These base substitution errors have very important implications for the biological consequences of genetic damage in non-dividing cells," Dr. Doetsch points out. "In some cases this miscoding could cause a cell to manufacture a mutant protein that controls cell division, which could take the cell from a non-growth state to a growth state and contribute to malignant transformation in the case of mammalian cells. Transcriptional mutagenesis in neurons could lead to neurodegenerative diseases."

Scientists already have learned that some genetic damages may block the transcription process, which is a signal for DNA repair molecules to move in and correct the mistake. When the DNA repair machinery is defective, however, the non-dividing cells are capable of continuing transcription despite the erroneous coding messages.

The Emory scientists present direct evidence that mutated proteins can be manufactured through this transcription pathway. They analyzed cells that were completely normal with respect to their DNA repair mechanisms as well as cells with various components of their DNA repair machinery eliminated. For some of the damages, when the repair machinery was intact, TM was very low, indicating that the purpose of DNA repair systems in non-dividing cells is to eliminate TM, Dr. Doetsch explains.

"Not only does this research show that genetic damages are capable of causing TM, it also identifies specific components of the cellular machinery whose job it is to repair damage from uracil and 8-oxoguanine to prevent TM from occurring," Dr. Doetsch explains. "The extent to which TM might occur for different kinds of genetic damages will depend on the cells' ability to repair damage before the transcriptional errors occur. This research also may allow us
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Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University Health Sciences Center
22-Oct-2003