Researchers from the Gothelf lab at
Triple helical structure provides protection and compactness
In nature, DNA is often made up of two strands that are twisted together into a double helix. One strand contains the genes responsible for encoding our traits and the other strand acts as a backup. These two strands are held together by certain bonds, called Watson-Crick interactions, which allow the two strands to recognize and bind to each other. In addition to these well-known interactions, there is a lesser-known type of interaction between DNA strands. These so-called normal or reverse Hoogsteen interactions allow a third strand to join and form a beautiful triple helical structure: a triplex (figure 2).
In the new article published in the scientific journal Advanced Materials, researchers from Gothelf’s laboratory at Aarhus University have introduced a simple method for organizing DNA strands. The method is based on the aforementioned Hoogsteen interactions. The research shows that using this method, DNA can be bent or “folded” in a way that creates compact structures. These structures can take various forms, from hollow two-dimensional shapes to dense three-dimensional constructions and everything in between. In fact, you can even create structures that resemble a potted flower. The researchers call their method triplex origami (figure 3).
Potential in gene therapy and beyond
Using triplex origami, scientists can achieve unprecedented control over the shape of DNA molecules, opening up new possibilities for research. Previous studies have suggested that triplex formation plays a role in the natural packaging of DNA in cells, and this study can help us learn more about this critical biological process.
The study also shows that triplex formation protects DNA from enzymatic degradation. The ability to compress and protect DNA using the triplex origami method could therefore be of great importance in gene therapy, where diseased cells are repaired by delivering a function they lack via a DNA package.
The amazing biological properties of DNA’s sequence and structure have already been utilized in nanotechnology, which has had an impact on medical treatments, diagnostics, and many other areas. “For the past four decades, DNA nanotechnology has relied almost exclusively on Watson-Crick base interactions to assemble single-stranded DNA and organize them into custom nanostructures.” Says Professor Kurt V. Gothelf. ” We now know that Hoogsteen interactions have the same potential to organize double-stranded DNA, which presents a significant conceptual expansion for the field.”
Gothelf and co-workers demonstrated that Hoogsteen-mediated folding is compatible with state-of-the-art Watson-Crick-based methods. Due to the comparative rigidity of double-stranded DNA, however, triplex origami structures require fewer starting materials. This allows larger structures to be formed at a significantly lower cost.
The new method has the limitation that triplex formation typically requires long stretches of a specific building block, called purine bases. Here the researchers have used artificial DNA sequences instead of natural genetic DNA. In the future, they will work towards overcoming this limitation.
Reference: “Folding Double-Stranded DNA into Designed Shapes with Triplex-Forming Oligonucleotides” by Cindy Ng, Anirban Samanta, Ole Aalund Mandrup, Emily Tsang, Sarah Youssef, Lasse Hyldgaard Klausen, Mingdong Dong, Minke A. D. Nijenhuis and Kurt V. Gothelf, 13 June 2023, Advanced Materials.
DOI: 10.1002/adma.202302497