Too much sugar in the blood, as seen in diabetes, can lead to harmful changes to important biological molecules like DNA. City of Hope researchers recently discovered how one such altered form of DNA causes genetic mutations that may lead to cancer and other life-threatening diseases.
|John Termini studies mutations that can result from high blood sugar levels such as those found in diabetes. (Photo by Markie Ramirez)|
In diabetes and certain other conditions, high levels of the sugar known as glucose drive the formation of damaging byproducts in the bloodstream. These substances react with molecules in cells. The reaction, called glycation, produces compounds that can lead to severe illnesses including kidney failure, nerve damage and other complications.
Some glycation products also may lead to cancer.
Scientists have focused heavily on protein glycation, the formation of harmful products when sugar interacts with proteins. But less is understood about molecules produced through DNA glycation. So researchers led by City of Hope’s John Termini, Ph.D., professor of molecular medicine, have turned their focus on a DNA glycation product called CEdG.
In previous research, the scientists found that CEdG interfered with cells’ ability to properly read their genetic code and replicate their DNA during growth.
“Our results suggested CEdG could cause genomic instability and mutations,” Termini said. “We wanted to confirm that and understand the mechanisms involved.”
To test their theory, the team genetically altered cells to contain different amounts of CEdG. They then compared the frequency of genetic mutations in those cells to normal, unaltered cells.
The scientists found that cells with CEdG had higher mutation levels than cells without it. Mutations often can disrupt normal cell function and lead to diseases, including cancer.
Seeking to understand how CEdG increased mutations, the researchers also tested cells that were manipulated to remove one of the tools cells use to fix their damaged DNA and prevent cancer. They found that CEdG produced far more mutations in these cells than in the other types.
The results not only showed that CEdG causes mutations, they pointed to the specific cellular tool — called nucleotide excision repair — as the main mechanism cells use to fix the damage CEdG causes.
The findings add to growing evidence linking the factors behind both cancer and metabolic diseases.
The study appeared in the Feb. 11 issue of Biochemistry. Other authors include Daniel Tamae, Ph.D., formerly a student in the Irell & Manella Graduate School of Biological Sciences, as well as Punnajit Lim, Ph.D., postdoctoral fellow, and Gerald E. Wuenschell, staff scientist, both in the Department of Molecular Medicine.