Oct. 23, 2003 ATLANTA -- Two types of DNA damage that frequently befall most cells on an everyday basis can lead to the creation of damaged proteins that may contribute to neurodegeneration, aging and cancer, according to research by scientists at Emory University School of Medicine, published in the October 23 issue of the journal Molecular Cell.
The investigators used e. coli cells as a model system to study specific kinds of genetic damages that occur in all non-dividing cells undergoing transcription –– the everyday activity in which cells produce the proteins necessary to carry out bodily processes. The vast majority of scientists studying genetic mutations have focused instead on the cell replication process, in which damaged and unrepaired DNA within multiplying cells can be copied before cells divide and passed along to a new generation of cells. Most of the cells within organisms are no longer replicating, however, and instead spend their time manufacturing proteins.
Paul W. Doetsch, PhD, professor of biochemistry at Emory University School of Medicine, lead author Damien Bregeon, PhD, an Emory postdoctoral fellow, and their colleagues discovered that in e.coli cells, two of the most frequently occurring spontaneous DNA damages that cells in all organisms are exposed to on a daily basis cause transcriptional mutagenesis (TM). TM occurs when cells with damaged DNA produce bad messages during transcription that lead to the creation of mutant proteins.
During transcription, cells make an RNA copy of the combinations of base sequences that make up the genes on the DNA molecule. This RNA copy serves as a blueprint for manufacturing particular proteins. One type of spontaneous genetic damage occurs in non-dividing cells when cytosine (C), one of the four amino-acid bases (A, T, G, and C) spontaneously changes to uracil (U). This common substitution causes genetic miscoding that can lead to TM and the manufacture of mutant proteins during transcription.
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 to devise explanations for physiological changes that occur in non-dividing cells exposed to damaging environmental agents.
"A number of studies, culminating in this one, show that DNA damages leading to TM are an important event that may account for the deleterious effects of unrepaired genetic damage. Although our study was in e.coli, very similar systems operate to repair genetic damage in human cells, thus this is a very important model for helping understand the mechanisms in non-dividing cells that can cause the manufacture of mutant proteins as a result of genetic damage to cells, says Dr. Doetsch."
Other contributors to the research were Bernard Weiss, PhD, Emory professor of pathology and laboratory medicine, Zara A. Doddridge, PhD, Emory postdoctoral fellow, and Ho Jin You, MD, PhD, from the Department of Pharmacology at Chosun University Medical School in the Republic of Korea.
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