• Wed. Dec 6th, 2023

Researchers capture atomic view of synthetic DNA, reveal ‘molecular scissors’ that could treat disease

Researchers capture atomic view of synthetic DNA, reveal ‘molecular scissors’ that could treat disease

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10-23 DNAzyme Crystallization Construction and Operation. 10-23 A secondary structure of a crystallization construct. Activity of the B10-23 crystallization construct is inhibited by a 2′-OMe substitution at the cleavage site (green dots indicate the location of the FAM label). Credit: Communications Chemistry (2023). DOI: 10.1038/s42004-023-00924-3

West Virginia University researchers can now look at synthetic DNA at the atomic level, giving them the ability to understand how to alter its structure in hopes of enhancing its scissor-like activity. Learning more about these synthetic DNA reactions could be the key to unlocking new technology for medical diagnostics and treatments.

In the world of chemistry, the findings help answer a 30-year-old question about this particular DNA structure, and how scientists can create a reaction without changing the DNA, a process called catalysis.

The researchers’ findings have been published Communications Chemistry.

“This is only the third example to provide detailed atomic-level insights into how chemically active DNA promotes their unique functions that power all of these applications,” said Aaron Robart, associate professor of biochemistry and molecular medicine in the WVU School of Medicine’s Department of Medicine and the project’s principal investigator. “Atomic details provide us with a long-sought road map to begin building and improving a technology broadly applicable to health and diagnostics.”

Once scientists figure out how to make the technology more efficient, Robart said, it could theoretically be applied as a treatment for diseases like retinal degeneration or cancer.

Sarah Starkovic, a West Virginia University doctoral student in biochemistry and molecular medicine from Cameron, conducts research in the lab of WVU School of Medicine Associate Professor Aaron Robart. The video includes more from Starkovic and others on work to see synthetic DNA at the atomic level. Credit: WVU / Hannah Maxwell

Robart points out that synthetic DNA, known as DNAzymes, is different from human DNA. DNAzymes created in a lab are inexpensive to produce and capable of catalyzing chemical reactions. They have been artificially developed to perform tasks such as monitoring air quality and measuring heavy metals in soil.

“Typically, we think of DNA as passive, acting as a storage unit for our genetic information,” Robart said. “However, certain types of DNA have been developed in the laboratory that defy conventional rules. These DNAs can fold into complex shapes, enabling them to perform remarkable reactions.

“The only problem is that after 30 years of research, we have no clue how the chemistry happens. One big thing we’re missing is what our lab is doing with the crystals, resulting in high-resolution structures of how nucleic acids look down to atomic detail.”

To see DNA at the atomic level, Robart and his lab students, Evan Kramer, in Lake Ann, Michigan; Sarah Starkovich of Cameron; Becca Avey of Martinsburg also collaborated with the Advanced Photon Source at the US Department of Energy’s Argonne National Laboratory in Chicago. Synthetic DNA is crystallized in a process called X-ray crystallography and then its structure is revealed using super-powered X-rays. Working with APS, the team was able to control X-rays and collect data via the Internet.

“Using this information, we can better understand how other DNAzymes behave in their cleavage reactions,” said Starkovic, who is pursuing a doctoral degree in biochemistry and molecular medicine.

Robart said they envisioned a structure with small arms that could find another part of a complementary sequence and attach itself, similar to how Velcro attaches.

“These DNAs can act as molecular scissors that are highly specialized for cutting RNA or DNA, or they can act as glue,” Robart explained. “Say you have a mutated gene that causes disease, we can deliver this DNA into cells, and it can get rid of all kinds of messages that trigger proteins that lead to disease.”

Kramer, lead author of the published paper and a doctoral student in biochemistry and molecular medicine, said future studies are expected to fill the knowledge gaps for clinical implementation.

“It’s hard to improve something when you don’t fully know how it works,” he said.

The next step, Robart said, is to focus on alternative techniques to capture DNAzymes at different stages of their activity.

“It’s like we’re making an old-school animated molecular flipbook,” Robart said. “This level of detail is being used to understand how to improve, target and regulate their activity. This is just one of hundreds of different types of DNAzymes, all begging for application in human health issues.”

He said he hopes to gain insight from School of Medicine colleagues on how to use the model systems for therapeutics.

“We’re in a unique position,” Robart said. “We have a potential cure for a disease. I feel fortunate to help push this exciting technology to its full potential in an environment surrounded by so many talented collaborators at the School of Medicine.”

More information:
Evan R. Kramer et al., structure of a 10-23 deoxyribozyme exhibiting a homodimer conformation, Communications Chemistry (2023). DOI: 10.1038/s42004-023-00924-3

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