Featured Research

from universities, journals, and other organizations

Misreading Of Damaged DNA May Spur Tumor Formation

Date:
November 21, 2008
Source:
Emory University
Summary:
Cells can turn on tumor-promoting growth circuits by falsely reporting critical genetic information during the process of transcription: making RNA from DNA. Damage to the DNA making up a gene can lead to a misreading of the gene as it is made into RNA, a process called transcriptional mutagenesis. Transcriptional mutagenesis could represent an additional way DNA damage contributes to tumor formation.

The DNA in our cells is constantly under assault from oxygen, the sun's radiation and environmental stresses. Most of the time, our cells can repair the damage before it gets copied into a permanent mutation that could lead to cancer.

Adding a wrinkle to our understanding of how cancers begin, scientists have found that cells can turn on tumor-promoting growth circuits as a result of misreading damaged DNA without copying it: a process called "transcriptional mutagenesis."

The results are published online this week in Proceedings of the National Academy of Sciences.

"This reveals a new aspect of tumor development that could be especially important for cells that make up most of the body's tissues: differentiated cells that are not replicating their DNA," says Paul Doetsch, PhD, professor of biochemistry at Emory University School of Medicine and deputy director of basic research at Emory Winship Cancer Institute.

All cells, including non-dividing cells that are not replicating their DNA, continue to transcribe, or make RNA, from some of their genes in order to produce proteins and carry out their normal functions.

Doetsch and postdoctoral researcher Tina Saxowsky, PhD, examined what happens when mouse cells are presented with DNA pre-loaded with a damaged building block in a critical place.

The DNA encoded the gene Ras, one of the genes most often mutated in human cancers. The damage came in the form of 8-oxoguanine, which is generated when guanine, one of the four bases making up DNA, reacts with oxygen. (The four bases are: Adenine, Guanine, Cytosine and Thymine.) Cells unable to repair the damage tend to replace the modified guanine (G) with thymine (T).

"It's one of the most common forms of genetic damage," Doetsch says. "Constantly dealing with oxidation is the price we pay for breathing air."

If the cells misread the G as T during the process of transcription, some of the Ras protein they make comes in the hyperactivated form found in cancers. By looking at other proteins controlled by Ras, the authors could detect some of the cell's growth circuits starting to turn on.

By reading the RNA the cells make from the Ras DNA, Saxowsky found that even normal mouse cells misread the damaged DNA about three percent of the time. Sometimes the cell's machinery sees the damaged G as T, and sometimes it skips a letter. However, the mouse cells were more likely to misread the 8-oxoguanine (14 percent of the time) if they came from mice engineered to lack an enzyme that normally repairs the damage, called 8-oxoguanine glycosylase.

Doetsch says his group's findings suggest that DNA damage, if it hits certain critical genes in a cell, could lead to transcriptional mutagenesis that in turn spurs the cell to divide.

"Let's say that DNA damage lands in a gene that normally prevents a cell from dividing when it's not supposed to," Doetsch says. "If enough mutant proteins get made from the gene, the cell divides and the DNA is copied. Now, in one of the daughter cells the damage becomes a permanent mutation driving further growth. It's another way for tumor promotion to happen, except the growth signal needed to push the process along isn't coming from a chemical or a hormone."

He and Saxowsky are performing additional experiments to test the hypothesis that transcriptional mutagenesis can lead to cell division directly.

Transcriptional mutagenesis could explain a phenomenon seen in bacteria called adaptive mutagenesis, Doetsch says. When faced with starvation conditions, bacteria can relax their standards of accuracy when copying their DNA, apparently in an effort to mutate their way out of a dead end.

It appears that bacterial enzymes that make RNA from DNA are more susceptible to transcriptional mutagenesis than those from mammals, Doetsch notes, but further studies are required.

Cancer is essentially the "selfish" growth of a small group of cells at the expense of the person they came from, an issue that does not arise in one-celled organisms such as bacteria, he says.

The research was funded by the National Institutes of Health.


Story Source:

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


Journal Reference:

  1. Saxowsky et al. 8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells. Proceedings of the National Academy of Sciences, 2008; DOI: 10.1073/pnas.0806464105

Cite This Page:

Emory University. "Misreading Of Damaged DNA May Spur Tumor Formation." ScienceDaily. ScienceDaily, 21 November 2008. <www.sciencedaily.com/releases/2008/11/081120130604.htm>.
Emory University. (2008, November 21). Misreading Of Damaged DNA May Spur Tumor Formation. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2008/11/081120130604.htm
Emory University. "Misreading Of Damaged DNA May Spur Tumor Formation." ScienceDaily. www.sciencedaily.com/releases/2008/11/081120130604.htm (accessed October 21, 2014).

Share This



More Health & Medicine News

Tuesday, October 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

CDC Revamps Ebola Guidelines After Criticism

CDC Revamps Ebola Guidelines After Criticism

Newsy (Oct. 21, 2014) The Centers for Disease Control and Prevention have issued new protocols for healthcare workers interacting with Ebola patients. Video provided by Newsy
Powered by NewsLook.com
WHO: Ebola Vaccine Trials to Start a in January

WHO: Ebola Vaccine Trials to Start a in January

AP (Oct. 21, 2014) Tens of thousands of doses of experimental Ebola vaccines could be available for "real-world" testing in West Africa as soon as January as long as they are deemed safe in soon to start trials, the World Health Organization said Tuesday. (Oct. 21) Video provided by AP
Powered by NewsLook.com
First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

Newsy (Oct. 21, 2014) A medical team has for the first time given a man the ability to walk again after transplanting cells from his brain onto his severed spinal cord. Video provided by Newsy
Powered by NewsLook.com
CDC Issues New Ebola Guidelines for Health Workers

CDC Issues New Ebola Guidelines for Health Workers

Reuters - US Online Video (Oct. 21, 2014) The U.S. Centers for Disease Control and Prevention has set up new guidelines for health workers taking care of patients infected with Ebola. Linda So reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins