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.