Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Common genetic damages in non-dividing cells lead to the creation of mutant proteins

23.10.2003


’Transcriptional Mutagenesis’ may contribute to neurodegenerative diseases, cancer, and aging



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.

Holly Korschun | EurekAlert!
Further information:
http://www.emory.edu/

More articles from Health and Medicine:

nachricht 'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers
16.02.2018 | National University of Science and Technology MISIS

nachricht New process allows tailor-made malaria research
16.02.2018 | Eberhard Karls Universität Tübingen

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Japanese researchers develop ultrathin, highly elastic skin display

19.02.2018 | Information Technology

Dispersal of Fish Eggs by Water Birds – Just a Myth?

19.02.2018 | Ecology, The Environment and Conservation

Studying mitosis' structure to understand the inside of cancer cells

19.02.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>