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Emory University Scientists Demonstrate New Pathway For Genetic Mutations In Everyday Cell Life

Date:
April 6, 1999
Source:
Emory University Health Sciences Center
Summary:
Spontaneous chemical changes occurring within the DNA of non-dividing cells may result in the development of mutant proteins with potentially serious consequences for the development of degenerative neurological diseases or cancer. Findings by Emory University scientist Paul Doetsch, Ph.D., reported in the April 2, 1999 issue of Science, provide a new explanation for why and how terminally differentiated cells -- those that are no longer dividing and replicating -- express unrepaired genetic damage.

Spontaneous chemical changes occurring within the DNA of non-dividing cells may result in the development of mutant proteins with potentially serious consequences for the development of degenerative neurological diseases or cancer. Findings by Emory University scientist Paul Doetsch, Ph.D., reported in the April 2, 1999 issue of Science, provide a new explanation for why and how terminally differentiated cells -- those that are no longer dividing and replicating -- express unrepaired genetic damage. Co-authors of the study were graduate student Anand Viswanathan and Ho Jin You, M.D., Ph.D.

Most of the cells within the adult human body are no longer replicating, but are responsible for manufacturing the proteins necessary to carry out everyday bodily processes. Yet most research on cellular DNA damage and repair mechanisms has focused on the cell replication process, where damaged and unrepaired DNA can result in errors when DNA is copied before cells divide.

Dr. Doetsch and his colleagues concentrated on non-dividing cells, which go through a process called transcription in order to manufacture proteins. During transcription, the cell first makes an RNA copy of the DNA molecule by using an RNA polymerase -- a specialized protein that reads the DNA genetic code imprinted on one of the two DNA strands. The polymerase then turns the genetic code into an RNA genetic code. The base sequence code on the RNA, in turn, serves as a blueprint that "codes" for a particular protein.

The Emory investigators studied a particular type of spontaneous damage occurring in cytosine, one of the four amino-acid bases (A, T, G, and C) that are combined in different sequences within the DNA to make genes. In a common chemical change, cytosine may lose one of its components and change to uracil, a base that is normally found only in RNA. Since uracil (U) acts more like the T base than it does the C base, it causes genetic miscoding that can lead to protein mutations.

"Scientists have known for awhile that cytosine changing to uracil is a very important type of genetic damage in the process of cell division and DNA synthesis," Dr. Doetsch reports. "Because DNA serves as the master molecule that specifies coding information, if the uracil damage is not repaired, genetic mutations will result during replication. We asked the same questions about uracil damage from the point of view of transcription," he explains, "which is a very different way of thinking about how mutant proteins arise."

Scientists already know that some genetic damages that occur during transcription may block the action of polymerases, which is a signal for the DNA repair machinery to move in and correct the mistake. When polymerases are not blocked, however, non-dividing cells can continue the work of transcription, all the while reading an erroneous coding message.

"This base substitution error has very important implications for the biological consequences of genetic damage in non-dividing cells," Dr. Doetsch points out. "You can imagine situations where this miscoding could cause the cell to manufacture a mutant protein, and if that protein is the one controlling the fact that the cell is not dividing, it could take the cell from a non-growth state to a growth state, possibly contributing to malignant transformation in the case of mammalian cells."

"The findings also have implications for a number of other things, including age-related cell death in cells that do not normally divide -- like neurons, for example, which could lead to neurodegenerative diseases."

"This experiment was the 'proof of principle' that this kind of pathway could occur in live cells," explains Dr. Doetsch. "The extent to which this would occur for different varieties of genetic damages will probably depend on the cells' ability to repair genetic damage and on what part of the growth state or non-growth state the cells were in. This research may allow us to devise explanations for how physiological changes might occur in non-dividing cells that are exposed to environmental agents that damage the genome or even the cells' own processes that spontaneously change the DNA."

In order to demonstrate that the uracil substitution could occur in vivo (within live organisms) as well as in vitro (in a test tube), the Emory scientists used the protein luciferase -- which emits the light that makes fireflies glow -- as a "reporter" to measure the effects of DNA damage on cells.

They inserted the luciferase gene into two different types of E. coli cells along with a special chemical that kept the cells from dividing. They then altered the luciferase gene by substituting uracil for cytosine. One kind of E. coli cell was able to repair the uracil lesions, but the other one lacked the appropriate repair enzyme and was not able to correct the mistake. As long as the damage was repaired, no glowing luciferase protein could be detected, but when the cells were unable to repair the DNA damage, luciferase was manufactured and could be detected.


Story Source:

The above story is based on materials provided by Emory University Health Sciences Center. Note: Materials may be edited for content and length.


Cite This Page:

Emory University Health Sciences Center. "Emory University Scientists Demonstrate New Pathway For Genetic Mutations In Everyday Cell Life." ScienceDaily. ScienceDaily, 6 April 1999. <www.sciencedaily.com/releases/1999/04/990406043745.htm>.
Emory University Health Sciences Center. (1999, April 6). Emory University Scientists Demonstrate New Pathway For Genetic Mutations In Everyday Cell Life. ScienceDaily. Retrieved August 29, 2014 from www.sciencedaily.com/releases/1999/04/990406043745.htm
Emory University Health Sciences Center. "Emory University Scientists Demonstrate New Pathway For Genetic Mutations In Everyday Cell Life." ScienceDaily. www.sciencedaily.com/releases/1999/04/990406043745.htm (accessed August 29, 2014).

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