A vicious cycle of DNA damage and repair could be turned against cancer
Researchers at the University of North Carolina (UNC) have discovered that a common lab molecule, used to label DNA, can trigger a runaway process that eventually leads to cell death. But the team says this could have a positive use too, as a potential cancer treatment.
The molecule in question is known as 5-ethynyl-2′-deoxyuridine (EdU), which was designed as a chemical stand-in for thymidine, a key nucleoside in DNA. The advantage of EdU over the natural version or other alternatives is that it has a receptor that fluorescent molecules can easily bind to, allowing scientists to label DNA and track changes during processes like cell division.
However, EdU was known to be moderately toxic to cells, although the specific mechanism for that effect hadn’t been identified. In previous work the UNC team noticed that DNA that had been labeled with EdU seemed to invoke a repair response, even in the absence of triggers that normally damage DNA. So for the new study they investigated why that occurs, and found that it creates a feedback loop that can ultimately end with the death of a cell.
On closer inspection, the team found that the specific type of repair response invoked in EdU-tagged DNA is what’s called nucleotide excision repair. This common process is how DNA is repaired after exposure to things like UV light or cigarette smoke, and involves snipping out a section of damaged DNA and resynthesizing a new copy.
The researchers mapped out this excision repair, and found that it occurs wherever EdU is located across the whole genome. And it didn’t stop at just one time – the process was found to occur over and over again. That’s because the newly synthesized DNA strand also contained EdU, which triggered the same repair response.
This vicious cycle could explain EdU’s mysterious toxicity to cells. It traps them in a loop of constant DNA repair that can never “fix” the problem, until ultimately the cell triggers a self-destruct sequence instead.
The team says that this discovery has major implications for the use of EdU in DNA tagging, but it might also open up other breakthroughs as well. Because the molecule tends to select for cells that divide quickly, EdU could have anticancer properties. Brain cancer might be a particularly good target, since it’s a fast-growing clump of cells surrounded by healthy cells that have stopped dividing.
“The unexpected properties of EdU suggest it would be worthwhile to conduct further studies of its potential, particularly against brain cancers,” said Aziz Sancar, senior author of the study. “We want to stress that this is a basic but important scientific discovery. The scientific community has much work ahead to figure out if EdU could actually become a weapon against cancer.”
The research was published in the journal PNAS.