COMMON GENETIC DAMAGES IN NON-DIVIDING CELLS LEAD TO THE CREATION
OF MUTANT PROTEINS
Mutagenesis" May Contribute to Neurodegenerative Diseases, Cancer,
ATLANTATwo 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
"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