Scientists at the UNC School of Medicine have made the surprising discovery that a molecule called EdU, which is commonly used to label DNA in laboratory experiments, is actually recognized by human cells as DNA damage, triggering the escape process of DNA repair. Deadly for affected cells including cancer cells.
Search, published in Proceedings of the National Academy of SciencesGiven its toxicity and its selectivity for rapidly dividing cells, points to the possibility of using EdU as a basis for cancer therapy.
“The unexpected properties of EdU suggest that it would be worthwhile to conduct further studies of its potential, particularly against brain cancers,” said study senior author Aziz Sankar, MD, PhD, Sarah Graham Keenan Professor in the UNC School of Biochemistry and Biophysics. Medicine 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 to do to find out if EDU can actually become a weapon against cancer.”
EDU (5-ethynyl-2′-deoxyuridine) is essentially a popular scientific tool that was 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 convenient chemical “handle” to which fluorescent probe molecules will bind tightly. It can thus be used to label and track DNA relatively easily and efficiently, for example in the study 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. Sankar, who won the 2015 Nobel Prize in Chemistry for his groundbreaking work on DNA repair, is one such scientist. When his lab began using EdU, his team unexpectedly observed that EdU-labeled DNA triggered a DNA repair response even when exposed to DNA-damaging agents such as ultraviolet light.
“That was quite a shock,” Sankar said. “So we decided to explore it further.”
Following the strange observation, the team discovered that EdU, for reasons that are still unclear, alters DNA in a way that triggers a repair response called nucleotide excision repair. This process involves removing a short stretch of damaged DNA and resynthesizing the replacement strand. It is a mechanism for repairing damage caused by UV light, cigarette smoke, and DNA-altering chemo drugs. The researchers mapped EdU-induced excision repair at high resolution and found that it occurs throughout the genome, and that it apparently occurs repeatedly, as each new repair strand incorporates EdU and thus triggers a new repair response.
It was known that EdU is moderately toxic to cells, although the mechanism of its toxicity was a mystery. The team’s findings strongly suggest that EdU kills cells by inducing a runaway process of futile excision repair, which ultimately leads to the cell’s termination through a programmed cell-death process called apoptosis.
That finding was interesting in itself, Sancar said, because it suggested that researchers using EdU to label DNA needed to take into account its escape excision repair trigger.
“As we speak, hundreds and maybe thousands of researchers use EdU in laboratory experiments to study DNA replication and cell proliferation without knowing that human cells detect it as DNA damage,” Sankar 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, while in the brain, most healthy cells are non-dividing. Thus, in theory, EdU could kill rapidly-dividing cancer brain cells while sparing non-dividing, healthy brain cells.
Sancar and his team hope to pursue follow-up 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 followed up on those results,” Sankar said.