Scientists at the UNC School of Medicine have made the surprising discovery that a molecule called EdU, which is commonly used in laboratory experiments to label DNA, is actually recognized by human cells as DNA damage, triggering a runaway process. of DNA repair that is ultimately fatal to affected cells, including cancer cells.

The discovery, published in Proceedings of the National Academy of Sciencesshows the possibility of using EdU as a basis for cancer treatment, given its toxicity and selectivity for rapidly dividing cells.

“The unexpected properties of EdU suggest that it would be worthwhile to conduct further studies on its potential, particularly against brain cancer,” said senior study author Aziz Sancar, MD, PhD, the Sarah Graham Kenan Professor of Biochemistry and of Biophysics at the UNC School of Biophysics. MD and member of the UNC Lineberger Comprehensive Cancer Center. “We want to emphasize that this is a basic but important scientific discovery. The scientific community has a lot of work ahead of it to understand if EdU can really become a weapon against cancer.”

EdU (5-ethynyl-2′-deoxyuridine) is essentially a popular scientific tool first synthesized in 2008 as an analog or chemical mimic of the DNA building block thymidine — which represents the letter “T” in the DNA code for adenine. (A), cytosine (C), guanine (G) and thymine (T). Scientists add EdU to cells in lab experiments to replace thymidine in DNA. Unlike other thymidine analogs, it has a suitable chemical “handle” to which the fluorescent probe molecules will bind tightly. Thus, it can be used relatively easily and efficiently to label and trace DNA, for example in studies of the DNA replication process during cell division.

Since 2008, scientists have used EdU as a tool in this way, as published in thousands of studies. Sancar, who won the Nobel Prize in Chemistry in 2015 for his groundbreaking work on DNA repair, is one such scientist. When his lab started using EdU, his team unexpectedly found that EdU-labeled DNA triggered a DNA repair response even when it was not exposed to DNA-damaging agents such as ultraviolet light.

“That was a shock,” Sancar said. “So we decided to explore it further.”

After the strange observation, the team discovered that EdU, for reasons that are still unclear, changes DNA in a way that provokes a repair response called nucleotide excision repair. This process involves removing a short piece of damaged DNA and resynthesizing a replacement strand. This is the mechanism that repairs most damage from UV light, cigarette smoke, and DNA-altering chemotherapy. The researchers mapped EdU-induced excision repair at high resolution and found that it occurs throughout the genome, and apparently occurs again and again, as each new repair strand incorporates EdU and thus provokes the repair response again.

EdU was known to be moderately toxic to cells, although the mechanism of its toxicity had been a mystery. The team’s findings strongly suggest that EdU kills cells by triggering a runaway process of excision repair, which ultimately leads the cell to terminate itself through a programmed cell death process called apoptosis.

This finding was interesting in itself, Sancar said, because it suggested that researchers using EdU to label DNA should consider promoting runaway excision repair.

“As we speak, hundreds and possibly thousands of researchers are using EdU to study DNA replication and cell proliferation in laboratory experiments without knowing that human cells detect it as DNA damage,” Sancar said.

Sancar and colleagues also realized that EdU’s properties could make it the basis for an effective brain cancer drug, because EdU is incorporated into DNA only in actively dividing cells, whereas in the brain, most healthy cells do not divide. Thus, in principle, EdU could kill rapidly dividing cancer brain cells while sparing non-dividing, healthy brain cells.

Sancar and his team hope to pursue further collaborations with other researchers to investigate the properties of EdU as an anticancer agent.

“Previous studies have already found evidence that EdU kills cancer cells, including brain cancer cells, but surprisingly, no one has ever followed up on those results,” Sancar said.

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