Newswise — A human cell holds approximately 2 meters of DNA, storing the crucial genetic data of an individual. If all the DNA within a single person were unraveled and extended, it would cover an astonishing distance – sufficient to travel to the sun and return 60 times. To handle this remarkable amount of biological data, the cell condenses its DNA into compact chromosomes.
"According to co-corresponding author Minke A.D. Nijenhuis, envision DNA as a paper that contains our complete genetic instructions. To accommodate all this information within a tiny cell nucleus, the paper is intricately folded into a compact structure. However, to access the information, specific sections of the paper need to be unfolded and folded back. This spatial arrangement of our genetic code plays a vital role in life. Consequently, our aim was to develop a methodology enabling researchers to manipulate and examine the condensation of double-stranded DNA."
Triple helical structure provides protection and compactness
Native DNA typically consists of two strands: one strand encoding the genes and a complementary strand intertwined to form a double helix. The stability of the double helix is maintained by Watson-Crick interactions, facilitating the recognition and pairing of the two strands. However, there is another type of DNA interaction that is less familiar. Known as normal or reverse Hoogsteen interactions, these interactions enable a third strand to join, resulting in the formation of an exquisite triple helix (Figure 2).
In a recent publication featured in Advanced Materials, scientists from the Gothelf laboratory introduced a universal technique for arranging double-stranded DNA employing Hoogsteen interactions. The study unequivocally showcases the ability of triplex-forming strands to induce significant bending or "folding" of double-stranded DNA, resulting in compacted structures. These structures exhibit a wide range of appearances, varying from hollow two-dimensional shapes to intricate three-dimensional constructs, encompassing diverse intermediate forms, including a structure reminiscent of a potted flower. The researchers have aptly named their methodology "triplex origami" (Figure 3).
The groundbreaking technique of triplex origami grants scientists an unprecedented level of artificial control over the shape of double-stranded DNA, surpassing previous limits and unlocking novel avenues for exploration. This advancement has sparked suggestions that triplex formation might have a role in the natural compaction of genetic DNA. The findings from the present study hold the potential to shed light on this fundamental biological process, providing valuable insights into the mechanisms underlying DNA compaction in nature.
Potential in gene therapy and beyond
Furthermore, the research highlights that Hoogsteen-mediated triplex formation serves as a protective shield, safeguarding the DNA from enzymatic degradation. This notable feature of the triplex origami technique holds significant implications for gene therapy, a field where damaged cells are restored by introducing a piece of double-stranded DNA that carries the missing function. The ability to compact and safeguard DNA using this method could have far-reaching implications in enhancing the efficiency and effectiveness of gene therapy approaches.
The remarkable characteristics of DNA sequence and structure have found applications in nanoscale materials engineering, leading to advancements in various fields such as therapeutics, diagnostics, and more. Professor Kurt V. Gothelf emphasizes that traditional DNA nanotechnology has primarily relied on Watson-Crick base interactions to pair single DNA strands and construct tailored nanostructures over the past four decades. However, the recent discovery of the organizing potential of Hoogsteen interactions in double-stranded DNA represents a significant conceptual expansion for the field. This newfound understanding opens up exciting possibilities for utilizing Hoogsteen interactions in DNA nanotechnology, broadening the scope of design and organization principles in this field.
Gothelf and his colleagues have successfully shown that Hoogsteen-mediated folding can be integrated with existing Watson-Crick-based techniques. While double-stranded DNA provides a relatively rigid structure, the triplex origami method requires fewer starting materials compared to traditional approaches. As a result, larger structures can be created at significantly reduced costs. This cost-effectiveness, coupled with the compatibility of Hoogsteen interactions with existing methods, opens up new possibilities for the construction of complex and sizable DNA-based structures in various applications.
One limitation of the triplex origami method is that it typically relies on long stretches of purine bases within the double-stranded DNA for efficient triplex formation. As a result, the researchers have utilized artificial DNA sequences instead of natural genetic DNA in their experiments. However, they acknowledge this limitation and express their commitment to overcoming it in future endeavors. By exploring and developing strategies to enable triplex formation with natural genetic DNA, the researchers aim to expand the applicability and potential of the triplex origami method.
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